New monocyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel β-aryl-α-oxysubstituted alkylcarboxylic acids of the general formula (I),  
                 
their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. The present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention also relates to novel intermediates, processes for their preparation and their use in the preparation of compounds of formula (I).

FIELD OF THE INVENTION

The present invention relates to novel antiobesity andhypocholesterolemic compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates and pharmaceutically acceptable compositions containing them.More particularly, the present invention relates to novelβ-aryl-α-oxysubstituted alkylcarboxylic acids of the general formula(I), their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates and pharmaceuticallyacceptable compositions containing them.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their analogs, their derivatives, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, pharmaceutically acceptable solvatesand pharmaceutical compositions containing them.

The present invention also relates to novel intermediates, processes fortheir preparation and their use in the preparation of compounds offormula (I).

The compounds of the present invention lower total cholesterol (TC);increase high density lipoprotein (HDL) and decrease low densitylipoprotein (LDL), which have a beneficial effect on coronary heartdisease and atherosclerosis.

The compounds of general formula (I) are useful in reducing body weightand for the treatment and/or prophylaxis of diseases such ashypertension, coronary heart disease, atherosclerosis, stroke,peripheral vascular diseases and related disorders. These compounds areuseful for the treatment of familial hypercholesterolemia,hypertriglyceridemia, lowering of atherogenic lipoproteins, VLDL (verylow density lipoprotein) and LDL. The compounds of the present inventioncan be used for the treatment of certain renal diseases includingglomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis and nephropathy. The compounds of general formula (I)are also useful for the treatment and/or prophylaxis of insulinresistance (type II diabetes), leptin resistance, impaired glucosetolerance, dyslipidemia, disorders related to syndrome X such ashypertension, obesity, insulin resistance, coronary heart disease andother cardiovascular disorders. These compounds may also be useful asaldose reductase inhibitors, for improving cognitive functions indementia, treating diabetic complications, disorders related toendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy,pancreatitis, arteriosclerosis, retinopathy, xanthorna, inflammation andfor the treatment of cancer. The compounds of the present invention areuseful in the treatment and/or prophylaxis of the above said diseases incombination/con-comittant with one or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol, and probucol.

BACKGROUND OF THE INVENTION

Atherosclerosis and other peripheral vascular diseases are the majorcauses effecting the quality of life of millions of people. Therefore,considerable attention has been directed towards understanding theetiology of hypercholesterolemia and hyperlipidemia and development ofeffective therapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al., (Br. Med. J., 282 (1981), 1741-1744) have shown thatincrease in HDL-particles may decrease the number of sites of stenosisin coronary arteries of human, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo et al.,(Arteriosclerosis 6 (1986) 434-441) have shown by in vitro experimentthat HDL is capable of removing cholesterol from cells. They suggestthat HDL may deplete tissues of excess free cholesterol and transfer itto liver (Macikinnon et al., J. Biol. chem. 261 (1986), 2548-2552).Therefore, agents that increase HDL cholesterol would have therapeuticsignificance for the treatment of hypercholesterolemia and coronaryheart diseases (CHD).

Obesity is a disease highly prevalent in affluent societies and in thedeveloping world and is a major cause of morbidity and mortality. It isa state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyeffects the quality of a large population in the world. Insulinresistance is the diminished ability of insulin to exert its biologicalaction across a broad range of concentrations. In insulin resistance,the body secretes abnormally high amounts of insulin to compensate forthis defect; failing which, the plasma glucose concentration inevitablyrises and develops into diabetes. Among the developed countries,diabetes mellitus is a common problem and is associated with a varietyof abnormalities including obesity, hypertension, hyper-lipidemia (J.Clin. Invest., (1985) 75: 809-817; N. Engl. J. Med. (1987) 317: 350-357;J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest.,(1975) 68: 957-969) and other renal complications (See PatentApplication No. WO 95/21608). It is now increasingly being recognizedthat insulin resistance and relative hyperinsulinemia have acontributory role in obesity, hypertension, atherosclerosis and type 2diabetes mellitus. The association of insulin resistance with obesity,hypertension and angina has been described as a syndrome having insulinresistance as the central pathogenic link-Syndrome-X.

Hyperlipidemia is the primary cause for cardiovascular (CVD) and otherperipheral vascular diseases. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein)seen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help in preventing cardiovascular diseases.

Peroxisome proliferator activated receptors (PPAR) are members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell,(1995) 83: 803-812), whereas the alpha (α) isoform of PPAR (PPARα)mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4:291-296) thereby resulting in reduction of circulating free fatty acidin plasma (Current Biol. (1995) 5: 618-621). PPARα agonists have beenfound useful for the treatment of obesity (WO 97/36579). It has beenrecently disclosed that there exists synergism for the molecules, whichare agonists for both PPARα and PPARγ and suggested to be useful for thetreatment of syndrome X (WO 97/25042). Similar synergism between theinsulin sensitizer (PPARγ agonist) and HMG CoA reductase inhibitor hasbeen observed which may be useful for the treatment of atherosclerosisand xanthoma (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, (1994) 79,1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated, less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997)94, 237-241) and inhibition of expression of prostate cancer tissue(Cancer Research (1998) 58:3344-3352). This would be useful in thetreatment of certain types of cancer, which express PPARγ and could leadto a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases and such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci. (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto the PPAR agonist expression and therefore lower plasma leptinconcentrations. However, it has been recently disclosed that compoundshaving insulin sensitizing property also possess leptin sensitizationactivity. They lower the circulating plasma leptin concentrations byimproving the target cell response to leptin (WO/98/02159).

A few β-aryl-α-hydroxy propionic acids, their derivatives and theiranalogs have been reported to be useful in the treatment ofhyperglycemia and hypercholesterolemia. Some of such compounds describedin the prior art are outlined below:

i) U.S. Pat. No. 5,306,726, WO 91/19702 disclose several3-aryl-2-hydroxypropionic acid derivatives of general formulas (IIa) and(IIb) as hypolipidemic and hypoglycemic agents.

Examples of these compounds are shown in formulas (IIc) and (IId)

ii) International Patent Applications, WO 95/03038 and WO 96/04260disclose compounds of formula (IIe)

wherein R^(a) represents 2-benzoxazolyl or 2-pyridyl and R^(b) representCF₃, CH₂OCH₃ or CH₃. A typical example is(S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoicacid (IIf).

iii) International Patent Application Nos. WO 94/13650, WO 94/01420 andWO 95/17394 disclose the compounds of general formula (IIg)A¹-X—(CH₂)_(n)—O-A²-A³Y.R²   (IIg)wherein A¹ represents aromatic heterocycle, A² represents substitutedbenzene ring and A³ represents a moiety of formula (CH₂)_(m)—CH—(OR¹),wherein R¹ represents alkyl groups, m is an integer; X representssubstituted or unsubstituted N; Y represents C═O or C═S; R² representsOR³ where R³ may be alkyl, aralkyl, or aryl group; n represents aninteger in the range of 2-6.

An example of these compounds is shown in formula (IIh)

iv) International publication No. WO 99/08501 discloses compounds ofgeneral formula (IIi)

where X represents O or S; the groups R¹, R² and group R³ when attachedto the carbon atom, may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy,aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; R¹, R² along with theadjacent atoms to which they are attached may also form a 5-6 memberedsubstituted or unsubstituted cyclic structure containing carbon atomswith one or more double bonds, which may optionally contain one or moreheteroatoms selected from oxygen, nitrogen and sulfur; R³ when attachedto nitrogen atom represents hydrogen, hydroxy, formyl or optionallysubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylicacid derivatives, or sulfonic acid derivatives; the linking grouprepresented by —(CH₂)_(n)—O— may be attached either through nitrogenatom or through carbon atom where n is an integer ranging from 1-4; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁴ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, optionally substituted aralkyl group or forms abond together with the adjacent group R⁵; R⁵ represents hydrogen,hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionallysubstituted aralkyl or R⁵ forms a bond together with R⁴; R⁶ may behydrogen, optionally substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,heteroaralkyl groups, with a provision that R⁶ does not representhydrogen when R⁷ represents hydrogen or lower alkyl group; R⁷ may behydrogen or optionally substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkylgroups; Y represents oxygen or NR⁸, where R⁸ represents hydrogen, alkyl,aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkylgroups; R⁷ and R⁸ together may form a substituted or unsubstituted 5 or6 membered cyclic structure containing carbon atoms, which mayoptionally contain one or more heteroatoms selected from oxygen, sulfuror nitrogen. An example of these compounds is shown in formula (IIj)

v) European publication No. EP 0903343 discloses compounds of generalformula (IIk)

where A is an alkylene, alkyleneoxy or alkylenecarbonyl, X is O, S, NHor CH₂; Y¹ is an amino, hydroxylamino, hydroxyalkylamino,monoalkylamino, dialkylamino, cyclic amino, hydroxy or lower alkoxygroup; R¹ is a hydrogen atom, lower alkyl, hydroxyalkyl group,alkoxyalkyl, halogenalkyl or CoY², where Y² is amino, hydroxyamino,hydroxyalkylamino, monoalkylamino, dialkylamino, cyclic amino, hydroxyor lower alkoxy group; R² is lower alkyl, hydroxyalkyl, alkoxyalkyl orhalogenalkyl group, COY²or a phenyl, pyridyl or aralkyl which may besubstituted and R³ is a hydrogen or halogen, alkyl, alkoxy,halogenalkyl, amino, hydroxy or acyl groups or a salt thereof; W is amonocyclic or cyclic lactam ring selected from the following groupswhich may be substituted:

wherein R⁴ is a hydrogen, halogen, alkyl, alkoxy, halogenalkyl, amino,hydroxy, cyano, carbonyl, acyl, nitro, carboxy or sulfonamide, phenyl orbenzyl which may be substituted; R⁵ is a hydrogen, alkyl, aryl, aralkylor pyridyl which may be substituted; R⁶ is hydrogen or lower alkyl groupR⁷ is a lower alkyl, phenyl or aralkyl groups; Z¹ is O, S, CH₂ or NR⁵,Z² is N or CH and m is an integer of 1 to 4.

An example of these compounds is shown in formula (IIl)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for lowering cholesteroland reducing body weight with beneficial effects in the treatment and/orprophylaxis of diseases related to increased levels of lipids,atherosclerosis, coronary artery diseases, Syndrome-X, impaired glucosetolerance, insulin resistance, insulin resistance leading to type 2diabetes and diabetes complications thereof, for the treatment ofdiseases wherein insulin resistance is the pathophysiological mechanismand for the treatment of hypertension, with better efficacy, potency andlower toxicity, we focussed our research to develop new compoundseffective in the treatment of the above mentioned diseases. Effort inthis direction has led to compounds having general formula (I).

The main objective of the present invention is therefore, to providenovel β-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them, or their mixtures.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric. forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures which may have agonist activity against PPARα and/orPPARγ, and optionally inhibit HMG CoA reductase, in addition to havingagonist activity against PPARα and/or PPARγ.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures having enhanced activities, without toxic effect or withreduced toxic effect.

Yet another objective of the present invention is a process for thepreparation of novel β-aryl-α-oxysubstituted alkylcarboxylic acids offormula (I), their derivatives, their analogs, their tautomeric forms,their stereoisomers, their polymorphs, their pharmaceutically acceptablesalts and their pharmaceutically acceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their analogs, their derivatives, their tautomers, theirstereoisomers, their polymorphs, their salts, solvates or their mixturesin combination with suitable carriers, solvents, diluents and othermedia normally employed in preparing such compositions.

Another objective of the present invention is to provide novelintermediates, a process for their preparation and their use in thepreparation of β-aryl-α-oxysubstituted alkyl carboxylic acids of formula(I), their derivatives, their analogs, their tautomers, theirstereoisomers, their polymorphs, their salts and their pharmaceuticallyacceptable solvates.

DETAILED DESCRIPTION OF THE INVENTION

β-aryl α-oxysubstituted propionic acids, their derivatives and theiranalogs of the present invention have the general formula (I)

where X represents O or S; the groups R¹, R² and the group R³ whenattached to the carbon atom, may be same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; R³ when attached to nitrogen atom representshydrogen, hydroxy, formyl or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives or sulfonic acid derivatives; the linkinggroup represented by —(CH₂)_(n)—O— may be attached either throughnitrogen atom or through carbon atom where n is an integer ranging from1-4; Ar represents a substituted or unsubstituted, divalent, single orfused, aromatic or heterocyclic group; R⁴ represents hydrogen atom,halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstitutedaralkyl group or forms a bond together with the adjacent group R⁵; R⁵represents hydrogen, hydroxy, halogen, lower alkyl, alkoxy, acyl,substituted or unsubstituted aralkyl or R⁵ forms a bond together withR⁴; R⁶ may be hydrogen atom or substituted or unsubstituted groupsselected from alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl groups, with a provision that R⁶does not represent hydrogen when R⁷ represents hydrogen or lower alkylgroup; R⁷ may be hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups; Y represents oxygen or NR⁸, where R⁸ representshydrogen, or substituted or unsubstituted groups selected from alkyl,aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkylgroups; R⁷ and R⁸ together may form a substituted or unsubstituted 5 or6 membered cyclic structure containing carbon atoms, a nitrogen atom andmay optionally contain one or more additional heteroatoms selected fromoxygen, sulfur or nitrogen.

Suitable groups represented by R¹, R² and the group R³ when attached tocarbon atom may be selected from hydrogen, halogen atom such asfluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, formyl;substituted or unsubstituted (C₁-C₁₂)alkyl group, especially, linear orbranched (C₁-C₁₀)alkyl group, such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl,heptyl, octyl and the like; cyclo(C₃-C₆)alkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl groupmay be substituted; (C₁-C₆)alkoxy such as methoxy, ethoxy, propyloxy,butyloxy, iso-propyloxy and the like, the alkoxy group may besubstituted; cyclo(C₃-C₆)alkoxy group such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, thecycloalkoxy group maybe substituted; aryl group such as phenyl, naphthyland the like, the aryl group may be substituted; aryloxy group such asphenoxy, naphthyloxy and the like, the aryloxy group may be substituted;aralkyl such as benzyl, phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and thelike, the aralkyl group may be substituted and the substituted aralkylis a group such as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂and the like; aralkoxy group such as benzyloxy, phenethyloxy,naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group maybe substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclylgroup may be substituted; heteroaryl group such as pyridyl, thienyl,furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroarylgroup may be substituted; heteroaralkyl group such as furanmethyl,pyridinemethyl, oxazolemethyl, oxazolethyl and the like, theheteroaralkyl group may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are asdefined earlier and may be substituted; acyl group such as acetyl,propionyl, benzoyl and the like, the acyl group may be substituted;acyloxy group such as OOCMe, OOCEt, OOCPh and the like which may besubstituted; hydroxy(C₁-C₆)alkyl, which may be substituted; amino;acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇, NHCOC₆H₅, and thelike, which may be substituted; mono(C₁-C₆)alkylamino group such asNHCH₃, NHC₂H₅, NHC₃H₇, NHC₆H₁₃ and the like, which may be substituted;(C₁-C₆)dialkylamino group such as N(CH₃)₂, NCH₃(C₂H₅) and the like,which may be substituted; arylamino group such as HNC₆H₅, NCH₃(C₆H₅),NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may be substituted;aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and thelike, which may be substituted; amino(C₁-C₆)alkyl, which may besubstituted; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl andthe like, which may be substituted; aryloxycarbonyl group such asphenoxycarbonyl, naphthyloxycarbonyl and the like, which may besubstituted; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may besubstituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl and the like, the alkoxyalkyl groups may besubstituted; aryloxyalkyl group such as C₆H₅OCH₂, C₆H₅OCH₂CH₂,naphthyloxymethyl and the like, which may be substituted; aralkoxyalkylgroup such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like, which may besubstituted; thio(C₁-C₆)alkyl, which may be substituted;(C₁-C₆)alkylthio, which may be substituted; alkoxycarbonylamino groupsuch as NHCOOC₂H₅, NHCOOCH₃ and the like, which may be substituted;aryloxycarbonylamino group such as NHCOOC₆H₅, NCH₃COOC₆H₅, NC₂H₅COOC₆H₅,NHCOOC₆H₄CH₃, NHCOOC₆H₄OCH₃ and the like, which may be substituted;aralkoxycarbonylamino group such as NHCOOCH₂C₆H₅, NHCOOCH₂CH₂C₆H₅,N(CH₃)COOCH₂C₆H₅, N(C₂H₅)COOCH₂C₆H₅, NHCOOCH₂C₆H₄CH₃, NHCOOCH₂C₆H₄OCH₃and the like, which may be substituted; carboxylic acid or itsderivatives such as amides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂,CONHPh and the like, or esters such as COOCH₃, COOC₂H₅, COOC₃H₇ and thelike, the carboxylic acid derivatives may be substituted; sulfonic acidor its derivatives such as amides like SO₂NH₂, SO₂NHMe, SO₂NMe₂,SO₂NHCF₃ and the like, or esters such as SO₂CH₃, SO₂C₂H₅, SO₂C₃H₇ andthe like, the sulfonic acid derivatives may be substituted.

When the groups represented by R¹, R² and the group R³ when attached tocarbon atom are substituted, the substituents may be selected fromhalogen, hydroxy, nitro or substituted or unsubstituted groups selectedfrom alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy,aralkoxy, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl,acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl,alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

It is preferred that the substituents on R¹ to R³ represent halogen atomsuch as fluorine, chlorine, bromine, hydroxy group, optionallyhalogenated groups selected from alkyl group such as methyl, ethyl,isopropyl, n-propyl, n-butyl; cycloalkyl group such as cyclopropyl; arylgroup such as phenyl; aralkyl group such as benzyl; (C₁-C₃)alkoxy,benzyloxy, acyl or acyloxy groups.

Suitable R³ when attached to nitrogen atom is selected from hydrogen,hydroxy, formyl; substituted or unsubstituted (C₁-C₁₂)alkyl group,especially, linear or branched (C₁-C₆)alkyl group, such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl,iso-pentyl, hexyl and the like; cyclo(C₃-C₆)alkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, thecycloalkyl group may be substituted; (C₁-C₆)alkoxy such as methoxy,ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, the alkoxygroup may be substituted; cyclo(C₃-C₆)alkoxy group such ascyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike, the cycloalkoxy group may be substituted; aryl group such asphenyl, naphthyl and the like, the aryl group may be substituted;aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxygroup may be substituted; aralkyl such as benzyl, phenethyl,C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, the aralkyl group may besubstituted and the substituted aralkyl is a group such as CH₃C₆H₄CH₂,Hal-C₆H₄CH₂. CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like; aralkoxy groupsuch as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy andthe like, the aralkoxy group may be substituted; heterocyclyl groupssuch as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyland the like, the heterocyclyl group may be substituted; heteroarylgroup such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and thelike, the heteroaryl group may be substituted; heteroaralkyl group suchas furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are asdefined earlier and may be substituted; acyl group such as acetyl,propionyl, benzoyl and the like, the acyl group may be substituted;acyloxy group such as OOCMe, OOCEt, OOCPh and the like which may besubstituted; hydroxy(C₁-C₆)alkyl, which may be substituted; amino;acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇, NHCOC₆H₅, whichmay be substituted; mono(C₁-C₆)alkylamino group such as NHCH₃, NHC₂H₅,NHC₃H₇, NHC₆H₁₃ and the like, which may be substituted;(C₁-C₆)dialkylamino group such as N(CH₃)₂, NCH₃(C₂H₅)and the like, whichmay be substituted; arylamino group such as HNC₆H₅, NCH₃(C₆H₅),NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may be substituted;aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and thelike, which may be substituted; amino(C₁-C₆)alkyl, which may besubstituted; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl andthe like, which may be substituted; aryloxycarbonyl group such asphenoxycarbonyl, naphthyloxycarbonyl and the like, which may besubstituted; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may besubstituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl and the like, the alkoxyalkyl groups may besubstituted; aryloxyalkyl group such as C₆H₅OCH₂, C₆H₅OCH₂CH₂,naphthyloxymethyl and the like, which may be substituted; aralkoxyalkylgroup such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like, which may besubstituted; thio(C₁-C₆)alkyl, which may be substituted;(C₁-C₆)alkylthio, which may be substituted; carboxylic acid derivativessuch as amides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh andthe like or esters such as COOCH₃, COOC₂H₅, COOC₃H₇ and the like, thecarboxylic acid derivatives may be substituted; sulfonic acidderivatives such as amides like SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ andthe like or esters such as SO₂CH₃, SO₂C₂H₅, SO₂C₃H₇ and the like, thesulfonic acid derivatives may be substituted.

When the groups represented by R³ attached to nitrogen are substituted,preferred substituents may be selected from halogen such as fluorine,chlorine; hydroxy, acyl, acyloxy, or amino groups.

n is an integer ranging from 1-4. It is preferred that n be 1 or 2.

Suitable groups represented by Ar include substituted or unsubstitutedgroups selected from divalent phenylene, naphthylene, pyridyl,quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl,indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl,benzoxazolyl and the like. The substituents on the group represented byAr may be selected from substituted or unsubstituted linear or branched(C₁-C₆)alkyl, (C₁-C₃)alkoxy, halogen, acyl, amino, acylamino, thio orcarboxylic or sulfonic acids and their derivatives.

It is preferred that Ar represents substituted or unsubstituted divalentphenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl,azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl.

It is more preferred that Ar is represented by divalent phenylene ornaphthylene, which may be optionally substituted by methyl, halomethyl,methoxy or halomethoxy groups.

Suitable R⁴ includes hydrogen, halogen atom such as fluorine, chlorine,bromine, or iodine; lower alkyl groups such as methyl, ethyl or propyl;hydroxy, (C₁-C₃)alkoxy such as methoxy, ethoxy, propoxy and the like;substituted or unsubstituted aralkyl such as benzyl, phenethyl and thelike or R⁴ together with R⁵ represent a bond.

Suitable R⁵ may be hydrogen, hydroxy, halogen atom such as fluorine,chlorine, bromine, or iodine; lower alkyl groups such as methyl, ethylor propyl; (C₁-C₃)alkoxy such as methoxy, ethoxy, propoxy and the like;acyl group such as linear or branched (C₂-C₁₀)acyl group such as acetyl,propanoyl, butanoyl, pentanoyl, benzoyl and the like; substituted orunsubstituted aralkyl such as benzyl, phenethyl and the like or togetherwith R⁴ forms a bond.

It is preferred that R⁴ and R⁵ represent hydrogen atom or R⁴ and R⁵together represent a bond.

Suitable groups represented by R⁶ may be selected from hydrogen,substituted or unsubstituted, linear or branched (C₁-C₁₆)alkyl,preferably (C₁-C₁₂)alkyl group such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like;substituted or unsubstituted, linear or branched(C₂-C₁₆)acyl group suchas acetyl, propanoyl, butanoyl, benzoyl, octanoyl, decanoyl and thelike; (C₃-C₇)cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like, the cycloalkyl group may besubstituted; aryl group such as phenyl, naphthyl and the like, the arylgroup may be substituted; aralkyl such as benzyl, phenethyl,C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, the aralkyl group may besubstituted and the substituted aralkyl is a group such as CH₃C₆H₄CH₂,Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like; heterocyclylgroup such as aziridinyl, pyrrolidinyl, piperidinyl and the like, theheterocyclyl group may be substituted; heteroaryl group such as pyridyl,thienyl, furyl and the like, the heteroaryl group may be substituted;heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl,oxazoleethyl and the like, the heteroaralkyl group may be substituted;(C₁-C₆)alkoxy(C₁-C₆)alkyl group such as methoxymethyl, ethoxymethyl,methoxyethyl, ethoxypropyl and the like, the alkoxyalkyl group may besubstituted; (C₁-C₆)alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and the like, which may be substituted;aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl and thelike, which may be substituted; (C₁-C₆)alkylaminocarbonyl,methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and thelike, which may be substituted; arylaminocarbonyl such as PhNHCO,naphthylaminocarbonyl and the like, which may be substituted. Thesubstituents may be selected from halogen, hydroxy, or nitro orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino,alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.

Suitable groups represented by R⁷ may be selected from hydrogen,substituted or unsubstituted, linear or branched (C₁-C₁₆)alkyl,preferably (C₁-C₁₂)alkyl group such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like;(C₃-C₇)cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and thelike, the cycloalkyl group may be substituted; aryl group such asphenyl, naphthyl and the like, the aryl group may be substituted;aralkyl group such as benzyl and phenethyl, the aralkyl group may besubstituted; heterocyclyl group such as aziridinyl, pyrrolidinyl,piperidinyl and the like, the heterocyclyl group may be substituted;heteroaryl group such as pyridyl, thienyl, furyl and the like, theheteroaryl group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like,the heteroaralkyl group may be substituted. The substituents on R⁷ maybe selected from the same group of R¹—R³.

Suitable groups represented by R⁸ may be selected from hydrogen,substituted or unsubstituted, linear or branched (C₁-C₁₆)alkyl,preferably (C₁-C₁₂)alkyl; aryl group such as phenyl, naphthyl and thelike, the aryl group may be substituted; hydroxy(C₁-C₆)alkyl which maybe substituted; aralkyl group such as benzyl and phenethyl and the like,the aralkyl group may be substituted; heterocyclyl group such asaziridinyl, pyrrolidinyl, piperidinyl, and the like, the heterocyclylgroup may be substituted; heteroaryl group such as pyridyl, thienyl,furyl and the like the heteroaryl group may be substituted;heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl,oxazoleethyl and the like, the heteroaralkyl group may be substituted.

Suitable ring structures formed by R⁷ and R⁸ together may be selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolinyl,diazolinyl and the like.

Suitable substituents on the cyclic structure formed by R⁷ and R⁸ takentogether may be selected from halogen, hydroxy, alkyl, oxo, aralkyl andthe like.

When any of the groups represented by R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Ar,R⁷, R⁸ or R⁷ and R⁸ taken together are substituted, the substituents areas defined above.

The compounds of formula (I) where R⁶represents hydrogen atom and R⁷represents hydrogen or lower alkyl groups have been described in ourU.S. Pat. Nos. 5,885,997 and 5,985,884.

Pharmaceutically acceptable salts forming part of this invention includesalts of the carboxylic acid moiety such as alkali metal salts like Li,Na, and K salts; alkaline earth metal salts like Ca and Mg salts; saltsof organic bases such as diethanolamine, choline and the like; chiralbases like alkylphenylamine, phenyl glycinol and the like, salts ofnatural amino acids such as lysine, arginine, guanidine, methionine,alanine, valine, and the like; unnatural amino acids such as D-isomersor substituted amino acids; ammonium or substituted ammonium salts andaluminum salts. Salts may include acid addition salts where appropriatewhich are, sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, succinates,palmoates, methanesulphonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprising other solvents of crystallization such asalcohols.

Particularly useful compounds according to the present inventioninclude:

(±)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[6-oxo-2-propyl-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[6-oxo-2-propyl-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[6-oxo-2-propyl-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl3-[4-[2-[2,5-diethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoate;

(+)Ethyl3-[4-[2-[2,5-diethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoate;

(−)Ethyl3-[4-[2-[2,5-diethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[2-isopropyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[2-isopropyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[2-isopropyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[4-methyl-6-oxo-2-propyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[4-methyl-6-oxo-2-propyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[4-methyl-6-oxo-2-propyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl3-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoate;

(+)Ethyl3-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoate;

(−)Ethyl3-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[1-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[1-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[1-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]ethoxy]phenyl]propanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-4-(4-fluoro)phenyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-4-(4-fluoro)phenyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-4-(4-fluoro)phenyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[4-(4-chloro)phenyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[4-(4-chloro)phenyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[4-(4-chloro)phenyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyljpropanoate;

(±)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(+)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(−)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate;

(±) 2-Ethoxy3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[6-oxo-2-propyl-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[6-oxo-2-propyl-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[6-oxo-2-propyl-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±)3-[4-[2-[2,5-Diethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoicacid or its salts;

(+)3-[4-[2-[2,5-Diethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoicacid or its salts;

(−)3-[4-[2-[2,5-Diethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[2-isopropyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[2-isopropyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[2-isopropyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[4-methyl-6-oxo-2-propyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[4-methyl-6-oxo-2-propyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[4-methyl-6-oxo-2-propyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±)3-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoicacid or its salts;

(+)3-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoicacid or its salts;

(−)3-[4-[2-[2,4-Dimethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-2-ethoxypropanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[2-ethyl-6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[2-ethyl-6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[2-ethyl-6-oxo-4-trifluoromethyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[1-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[1-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[1-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[2-ethyl-4-(4-fluoro)phenyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[2-ethyl-4-(4-fluoro)phenyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[2-ethyl-4-(4-fluoro)phenyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[4-(4-chloro)phenyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[4-(4-chloro)phenyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[4-(4-chloro)phenyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]yl]ethoxy]phenyl]propanoicacid or its salts;

(±) 2-Ethoxy3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(+) 2-Ethoxy3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

(−) 2-Ethoxy3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid or its salts;

[2 R, N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamideand

[2 S, N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide;

According to a feature of the present invention, the compound of generalformula (I) where R⁴ and R⁵ together represent a bond, Y representsoxygen atom, R¹, R², R³, R⁶, R⁷, X, n and Ar are as defined earlier, canbe prepared by any of the following routes shown in Scheme-I below.

Route (1): The reaction of a compound of the general formula (IIIa)where all symbols are as defined earlier with a compound of formula(IIIb) where R⁹ represents (C₁-C₆)alkyl and all other symbols are asdefined earlier to yield compound of general formula (I) where allsymbols are as defined above may be carried out in the presence of abase such as alkali metal hydrides like NaH or KH; organolithiums suchas CH₃Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K⁺BuO⁻ andthe like or mixtures thereof. The reaction may be carried out in thepresence of solvents such as THF, dioxane, DMF, DMSO, DME and the likeor mixtures thereof. HMPA may be used as cosolvent. The reactiontemperature may range from −78° C. to 50° C., preferably at atemperature in the range of −10° C. to 30° C. The reaction is moreeffective under anhydrous conditions. The compound of general formula(IIIb) may be prepared by Arbuzov reaction.

Alternatively, the compound of formula (I) may be prepared by reactingthe compound of formula (IIIa) where all symbols are as defined earlierwith Wittig reagents such as Hal⁻Ph₃P⁺CH—(OR⁶)CO₂R⁷ under similarreaction conditions as described above.

Route (2): The reaction of a compound of general formula (IIIc) whereall symbols are as defined earlier with a compound of general formula(IIId) where L¹ is a leaving group such as halogen atom,p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and thelike, preferably a halogen atom; R⁴, R⁵ together represent a bond andall other symbols are as defined earlier to produce a compound ofgeneral formula (I) where —(CH₂)_(n)— linker group is attached throughthe nitrogen atom and all other symbols are as defined above may becarried out in the presence of solvents such as DMSO, DMF, DME, THF,dioxane, ether and the like or mixtures thereof. The reaction may becarried out in an inert atmosphere which may be maintained by usinginert gases such as N₂, Ar, He and the like. The reaction may beeffected in the presence of a base such as alkalis like sodium hydroxideor potassium hydroxide; alkali metal carbonates such as sodium carbonateor potassium carbonate; alkali metal hydrides such as sodium hydride orpotassium hydride; organometallic bases like n-butyl lithium; alkalimetal amides like sodamide or mixtures thereof. The amount of base mayrange from 1 to 5 equivalents, based on the amount of the compound offormula (IIIc), preferably the amount of base ranges from 1 to 3equivalents. Phase transfer catalysts such as tetraalkylarnmonium halideor hydroxide may be added. Additives such as alkali metal halides suchas LiBr may be added: The reaction may be carried out at a temperaturein the range of 0° C. to 150° C., preferably at a temperature in therange of 15° C. to 100° C. The duration of the reaction may range from0.25 to 48 hours, preferably from 0.25 to 24 hours.

Route (3): The reaction of compound of general formula (IIIe) with acompound of general formula (IIIf) where R⁴, R⁵ together represent abond, L² is halogen, —OH, —R¹⁰, —O—C(═O)—OR¹⁰, where R¹⁰ is (C₁-C₅)alkyland all other symbols are as defined earlier to produce a compound ofgeneral formula (I) where —(CH₂)_(n)— linker group is attached throughthe carbon atom and all other symbols are as defined above may becarried out in the presence of solvents such as xylene, toluene, THF,dioxane, acetic acid, DMF, DMSO and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be carried out at a temperature in the range of 50° C. to200° C., preferably at a temperature in the range of 60° C. to 180° C.The reaction may be effected in the presence or in absence of a base oran acid. The nature of the base or the acid is not critical. Examples ofsuch bases include organic bases such as pyridine, lutidine, triethylamine, diisopropylethyl amine and the like; metal carbonates such asK₂CO₃ or Na₂CO₃. Examples of acids include organic acids such as AcOH,C₂H₅COOH, butyric acid, trifluoroacetic acid, p-toluenesulfonic acid,benzenesulfonic acid and the like; mineral acids such as HCl, HBr andthe like. The duration of the reaction may range from 0.25 to 48 hours,preferably from 0.50 to 18 hours.

Route (4): The reaction of a compound of the general formula (IIIa)where all symbols are as defined earlier, with a compound of formula(IIIg) where R⁵ represents hydrogen atom and all other symbols are asdefined earlier may be carried out in the presence of a base. The natureof the base is not critical. Any base normally employed for aldolcondensation reaction may be employed; bases like metal hydride such asNaH, KH, metal alkoxides such as NaOMe, t-BuO⁻K⁺, NaOEt, metal amidessuch as LiNH₂, LiN(ipr)₂ may be used. Aprotic solvents such as THF,ether, dioxane may be used. The reaction may be carried out in an inertatmosphere which may be maintained by using inert gases such as N₂, Ar,or He and the reaction is more effective under anhydrous conditions.Temperature in the range of −80° C. to 35° C. may be used. The β-hydroxyproduct initially produced may be dehydrated under conventionaldehydration conditions such as treating with pTSA in solvents such asbenzene or toluene. The nature of solvent and dehydrating agent is notcritical. Temperature in the range of 20° C. to reflux temperature ofthe solvent used may be employed, preferably at reflux temperature ofthe solvent by continuous removal of water using a Dean Stark waterseparator.

Route (5): The reaction of compound of formula (IIIh) where all symbolsare as defined earlier and L¹ represents a leaving group such as halogenatom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonateand the like, preferably a halogen atom with compound of formula (IIIi)where R⁴ and R⁵ together represent a bond and all other symbols are asdefined earlier to produce a compound of the formula (I) defined abovemay be carried out in the presence of aprotic solvents such as THF, DMF,DMSO, DME and the like or mixtures thereof. The reaction may be carriedout in an inert atmosphere which may be maintained by using inert gasessuch as N₂, Ar, He and the like. The reaction may be effected in thepresence of a base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof.Acetone may be used as solvent when Na₂CO₃ or K₂CO₃ is used as a base.The reaction temperature may range from 0° C.-120° C., preferably at atemperature in the range of 30° C.-100° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours. Thecompound of formula (IIIi) can be prepared according to known procedureby a Wittig Horner reaction between the hydroxy protected aryl aldehydesuch as benzyloxyaryl aldehyde and the compound of formula (IIIb),followed by deprotection.

Route (6): The reaction of compound of general formula (IIIj) where allsymbols are as defined earlier with a compound of general formula (IIIi)where R⁴ and R⁵ together represent a bond and all other symbols are asdefined earlier may be carried out using suitable coupling agents suchas dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such asPPh₃/DEAD and the like. The reaction may be carried out in the presenceof solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile,carbon tetrachloride and the like. The inert atmosphere may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of DMAP, HOBT and they may beused in the range of 0.05 to 2 equivalents, preferably 0.25 to 1equivalents. The reaction temperature may be in the range of 0° C. to100° C., preferably at a temperature in the range of 20° C. to 80° C.The duration of the reaction may range from 0.5 to 24 hours, preferablyfrom 6 to 12 hours.

Route (7): The reaction of a compound of formula (IIIk) where allsymbols are as defined earlier with a compound of formula (IIIl) whereR⁶═R⁷ and are as defined earlier excluding hydrogen, to produce acompound of the formula (I) where R⁴ and R⁵ together represent a bondmay be carried out neat in the presence of a base such as alkali metalhydrides like NaH, KH or organolithiums like CH₃Li, BuLi and the like oralkoxides such as NaOMe, NaOEt, t-BuO⁻K⁺ and the like or mixturesthereof. The reaction may be carried out in the presence of aproticsolvents such as THF, dioxane, DMF, DMSO, DME and the like or mixturesthereof. HMPA may be used as cosolvent. The reaction temperature mayrange from −78° C. to 100° C., preferably at a temperature in the rangeof −10° C. to 50° C.

Route (8): The cyclisation of a compound of general formula (IIIm),where R⁴ and R⁵ together represent a bond, R⁷ is as defined earlierexcluding hydrogen and all symbols are as defined earlier to produce acompound of general formula (I), where —(CH₂)_(n)— linker group isattached through nitrogen atom and all other symbols are as definedearlier may be carried out in neat or in the presence of solvents suchas xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like ormixtures thereof. The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar, He and thelike. The reaction may be carried out at a temperature in the range of50° C. to 200° C., preferably at a temperature in the range of 60° C. to180° C. The reaction may be effected in the presence or in absence of abase or an acid. The nature of the base or the acid is not critical.Examples of such bases include organic bases such as pyridine, lutidine,triethyl amine, diisopropylethyl amine and the like, metal carbonatessuch as K₂CO₃, Na₂CO₃. Examples of acids include organic acids such asAcOH, C₂H₅COOH, butyric acid, trifluoroacetic acid, p-toluenesulfonicacid, benzenesulfonic acid and the like, mineral acids such as HCl, HBrand the like. The duration of the reaction may range from 0.25 to 48hours, preferably from 0.50 to 18 hours.

In yet another embodiment of the present invention, the compound of thegeneral formula (I) where R⁴ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, substituted or unsubstituted aralkyl group; R⁵represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acylor substituted or unsubstituted aralkyl; R¹, R², R³, R⁶, R⁷, X, n and Arare as defined earlier and Y represents oxygen atom can be prepared byone or more of the processes shown in Scheme-II below.

Route (9): The reduction of compound of the formula (IVa) whichrepresents a compound of formula (I) where R⁴ and R⁵ together representa bond and Y represent oxygen atom and all other symbols are as definedearlier, obtained as described earlier (Scheme-1), to yield a compoundof the general formula (I) where R⁴ and R⁵ each represent hydrogen atomand all symbols are as defined earlier, may be carried out in thepresence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C,and the like. Mixtures of catalysts may be used. The reaction may alsobe conducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate, alcohol such as methanol, ethanol and the like. Apressure between atmospheric pressure and 80 psi may be employed. Thecatalyst may be preferably 5-10% Pd/C and the amount of catalyst usedmay range from 5-100% w/w. The reaction may also be carried out byemploying metal solvent reduction such as magnesium in alcohol or sodiumamalgam in alcohol, preferably methanol. The hydrogenation may becarried out in the presence of metal catalysts containing chiral ligandsto obtain a compound of formula (I) in optically active form. The metalcatalyst may contain Rhodium, Ruthenium, Indium and the like. The chiralligands may preferably be chiral phosphines such as optically pureenantiomers of 2,3-bis(diphenylphosphino)butane,1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane,2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane andthe like. Any suitable chiral catalyst may be employed which would giverequired optical purity of the product (I) (Ref: Principles ofAsymmetric Synthesis, Tetrahedron Series Vol 14, pp 311-316, Ed. BaldwinJ. E.).

Route (10): The reaction of compound of formula (IVb) where R⁷ is asdefined earlier excluding hydrogen all other symbols are as definedearlier and L³ is a leaving group such as halogen atom with an alcoholof general formula (IVc), where R⁶ is as defined earlier excludinghydrogen to produce a compound of the formula (I) defined earlier may becarried out in the presence of solvents such as THF, DMF, DMSO, DME andthe like or mixtures thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar, He and the like. The reaction may be effected in the presence ofa base such as KOH, NaOH, NaOMe, NaOEt, t-BuO⁻K⁺ or NaH or mixturesthereof. Phase transfer catalysts such as tetraalkylammonium halides orhydroxides may be employed. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-100° C.The duration of the reaction may range from 1 to 12 hours, preferablyfrom 2 to 6 hours. The compound of general formula (IVb) where R⁷represents hydrogen or lower alkyl group and its preparation has beendisclosed in our U.S. Pat. Nos. 5,885,997 and 5,985,884.

Route (11): The reaction of compound of formula (IIIh) defined earlierwith compound of formula (IIIi) where all symbols are as defined earlierto produce a compound of the formula (I) defined above, may be carriedout in the presence of solvents such as THF, DMF, DMSO, DME and the likeor mixtures thereof. The reaction may be carried out in an inertatmosphere which is maintained by using inert gases such as N₂, Ar, Heand the like. The reaction may be effected in the presence of a basesuch as K₂CO₃, Na₂CO₃, NaH and the like or mixtures thereof. Acetone maybe used as a solvent when K₂CO₃ or Na₂CO₃ is used as a base. Thereaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours. Thecompound of formula (IIIi) may be prepared by Wittig Homer reactionbetween the protected hydroxyaryl aldehyde and compound of formula(IIIj) followed by reduction of the double bond and deprotection.Alternatively, the compound of formula (IIIi) may be prepared byfollowing a procedure disclosed in WO 94/01420.

Route 12: The reaction of compound of general formula (IIIj) definedearlier with a compound of general formula (IIIi) where all symbols areas defined above may be carried out using suitable coupling agents suchas dicyclohexyl urea, driarylphosphine/dialkylazadicarboxylate such asPPh₃/DEAD and the like. The reaction may be carried out in the presenceof solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile,carbon tetrachloride and the like. The inert atmosphere may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of DMAP, HOBT and they may beused in the range of 0.05 to 2 equivalents, preferably 0.25 to 1equivalents. The reaction temperature may be in the range of 0° C. to100° C., preferably at a temperature in the range of 20° C. to 80° C.The duration of the reaction may range from 0.5 to 24 hours, preferablyfrom 6 to 12 hours.

Route 13: The reaction of compound of formula (IVd) which represents acompound of formula (I) where R⁶ represents hydrogen atom and all othersymbols are as defined above with a compound of formula (IVe) and is asdefined earlier excluding hydrogen and L³ is a halogen atom may becarried out in the presence of solvents such as THF, DMF, DMSO, DME andthe like. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar, He and the like. The reaction may be effected in thepresence of a base such as KOH, NaOH, NaOMe, t-BuO⁻K⁺, NaH and the like.Phase transfer catalyst such as tetraalkylammonium halides or hydroxidesmay be employed. The reaction temperature may range from 20° C. to 150°C., preferably at a temperature in the range of 30° C. to 100° C. Theduration of the reaction may range from 1 to 24 hours, preferably from 2to 6 hours.

The compound of formula (IVd) where R⁷ represents hydrogen or loweralkyl group and its preparation has been described in our U.S. Pat. Nos.5,885,997 and 5,985,884. The compound of formula (IVd) represents acompound of formula (I) where R⁶ represents hydrogen atom and all othersymbols are as defined earlier.

Route (14): The reaction of a compound of the general formula (IIIa) asdefined above with a compound of formula (IIIg) where R⁵ representshydrogen atom and all other symbols are as defined earlier may becarried out under conventional conditions. The base is not critical. Anybase normally employed for aldol condensation reaction may be employed,metal hydride such as NaH or KH; metal alkoxides such as NaOMe,t-BuO⁻K^(t) or NaOEt; metal amides such as LiNH₂, LiN(iPr)₂. Aproticsolvent such as THF may be used. Inert atmosphere may be employed suchas argon and the reaction is more effective under anhydrous conditions.Temperature in the range of −80° C. to 25° C. may be used. The β-hydroxyaldol product may be dehydroxylated using conventional methods,conveniently by ionic hydrogenation technique such as by treating with atrialkyl silane in the presence of an acid such as trifluoroacetic acid.Solvent such as CH₂Cl₂ may be used. Favorably, reaction proceeds at 25°C. Higher temperature may be employed if the reaction is slow.

Route (15): The reaction of a compound of general formula (IIIc) whereall symbols are as defined earlier with a compound of general formula(IIId) where L¹ is a leaving group such as halogen atom,p-toluenesulfonate, methanesulfonate, trifluoro-methanesulfonate and thelike, preferably a halogen atom and all other symbols are as definedearlier to produce a compound of general formula (I) where —(CH₂)_(n)—is attached through nitrogen atom and all other symbols are as definedabove may be carried out in the presence of solvents such as DMSO, DMF,DME, THF, dioxane, ether and the like or a combination thereof. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar, He and the like. Thereaction may be effected in the presence of a base such as alkalis likesodium hydroxide, potassium hydroxide; alkali metal carbonates likesodium carbonate or potassium carbonate; alkali metal hydrides such assodium hydride or potassium hydride; organometallic bases like n-butyllithium; alkali metal amides like sodamide or mixtures thereof. Theamount of base may range from 1 to 5 equivalents, based on the amount ofthe compound of formula (IIIc), preferably the amount of base rangesfrom 1 to 3 equivalents. Additives such as alkali metal halides such asLiBr may be added. The reaction may be carried out at a temperature inthe range of 0° C. to 150° C., preferably at a temperature in the rangeof 15° C. to 100° C. The duration of the reaction may range from 0.25 to48 hours, preferably from 0.25 to 24 hours.

Route (16): The reaction of compound of general formula (IIIe) asdefined earlier with a compound of general formula (IIIf) where L² ishalogen, —OH, —OR¹⁰, —O—C(═O)—OR¹⁰, where R¹⁰ is (C₁-C₅)alkyl and allother symbols are as defined earlier, to produce a compound of generalformula (I) where —(CH₂)_(n)— is attached through carbon atom and allother symbols are as defined above may be carried out in neat or in thepresence of solvents such as xylene, toluene, THF, dioxane, acetic acid,DMF, DMSO and the like or mixtures thereof. The reaction may be carriedout in an inert atmosphere which may be maintained by using inert gasessuch as N₂, Ar, He and the like. The reaction may be carried out at atemperature in the range of 50° C. to 200° C., preferably at atemperature in the range of 60° C. to 180° C. The reaction may beeffected in the presence or in absence of a base or an acid. The natureof the base or the acid is not critical. Examples of such bases includeorganic bases such as pyridine, lutidine, triethyl amine,diisopropylethyl amine and the like, metal carbonates such as K₂CO₃ orNa₂CO₃. Examples of acids include organic acids such as AcOH, C₂H₅COOH,butyric acid, trifluoroacetic acid, p-toluenesulfonic acid,benzenesulfonic acid and the like, mineral acids such as HCl, HBr andthe like. The duration of the reaction may range from 0.25 to 48 hours,preferably from 0.50 to 18 hours.

Route (17): The conversion of compound of formula (IVf) where allsymbols are as defined earlier to a compound of formula (I) may becarried out either in the presence of base or acid and the selection ofbase or acid is not critical. Any base normally used for hydrolysis ofnitrile to acid may be employed, metal hydroxides such as NaOH or KOH inan aqueous solvent or any acid normally used for hydrolysis of nitrileto ester may be employed such as dry HCl in an excess of alcohol such asmethanol, ethanol, propanol etc. The reaction may be carried out at atemperature in the range of 0° C. to reflux temperature of the solventused, preferably at a temperature in the range of 25° C. to refluxtemperature of the solvent used. The duration of the reaction may rangefrom 0.25 to 48 hrs.

Route (18): The reaction of a compound of formula (IVg) where R⁷ is asdefined earlier excluding hydrogen and all symbols are as definedearlier with a compound of formula (IVc) where R⁶ is as defined earlierexcluding hydrogen to produce a compound of formula (I) (by a rhodiumcarbenoid mediated insertion reaction) may be carried out in thepresence of rhodium (II) salts such as rhodium (II) acetate. Thereaction may be carried out in the presence of solvents such as benzene,toluene, dioxane, ether, THF and the like or a combination thereof orwhen practicable in the presence of R⁶OH as solvent at any temperatureproviding a convenient rate of formation of the required product,generally at an elevated temperature, such as reflux temperature of thesolvent. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar, He and the like. The duration of the reaction may rangefrom 0.5 to 24 h, preferably from 0.5 to 6 h.

Route (19): The cyclisation of compound of general formula (IIIm), whereR⁷ is as defined earlier excluding hydrogen and all other symbols are asdefined above and all other symbols are as defined earlier to produce acompound of general formula (I), where —(CH₂)_(n)— linker group isattached through nitrogen atom and all other symbols are as definedearlier may be carried out in neat or in the presence of solvents suchas xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like ormixtures thereof. The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar, He and thelike. The reaction may be carried out at a temperature in the range of50° C. to 200° C., preferably at a temperature in the range of 60° C. to180° C. The reaction may be effected in the presence or in absence of abase or an acid. The nature of the base or the acid is not critical.Examples of such bases include organic bases such as pyridine, lutidine,triethyl amine, diisopropylethyl amine and the like, metal carbonatessuch as K₂CO₃ or Na₂CO₃. Examples of acids include organic acids such asAcOH, C₂H₅COOH, butyric acid, trifluoroacetic acid, p-toluenesulfonicacid, benzenesulfonic acid and the like, mineral acids such as HCl, HBrand the like. The duration of the reaction may range from 0.25 to 48hours, preferably from 0.50 to 18 hours.

The compound of general formula (I) where R⁷ represents hydrogen atommay be prepared by hydrolysing using conventional methods, a compound offormula (I) where R⁷ represents all groups defined earlier excepthydrogen. The hydrolysis may be carried out in the presence of a basesuch as Na₂CO₃ and a suitable solvent such as methanol, ethanol and thelike or mixtures thereof. The reaction may be carried out at atemperature in the range of 20-120° C., preferably at 25-30° C. Thereaction time may range from 2 to 48 h, preferably from 4 to 12 h.

The compound of general formula (I) where Y represents oxygen and R⁷ isas defined earlier may be converted to compound of formula (I), where Yrepresents NR⁸ by reaction with appropriate amines. Suitably thecompound of formula (I) where YR⁷ represents OH may be converted to acidhalide, preferably YR⁷=halogen, by reacting with appropriate reagentssuch as oxalyl chloride, thionyl chloride and the like, followed bytreatment with amines; Alternatively, mixed anhydrides may be preparedfrom compound of formula (I) where YR⁷ represents OH and all othersymbols are as defined earlier by treating with acid halides such acetylchloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chlorideand the like. The reaction may be carried out in the presence ofsuitable base such as pyridine, triethylamine, diisopropyl ethylamineand the like. Solvents such as halogenated hydrocarbons like CHCl₃,CH₂Cl₂, hydrocarbons such as benzene, toluene, xylene and the like maybe used. The reaction may be carried out at a temperature in the rangeof −40° C. to 40° C., preferably 0° C. to 20° C. The acid halide ormixed anhydride thus prepared may further be treated with appropriateamines.

In another embodiment of the present invention there is provided thenovel intermediates of formula (IVf)

where X represents O or S; the groups R¹, R² and the group R³ whenattached to the carbon atom, may be same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; R³ when attached to nitrogen atom representshydrogen, hydroxy, formyl or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives or sulfonic acid derivatives; the linkinggroup represented by —(CH₂)_(n)—O— may be attached either throughnitrogen atom or through carbon atom where n is an integer ranging from1-4; Ar represents a substituted or unsubstituted, divalent, single orfused, aromatic or heterocyclic group; R⁴ represents hydrogen atom,halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstitutedaralkyl group or forms a bond together with the adjacent group R⁵; R⁵represents hydrogen, hydroxy, halogen, lower alkyl, alkoxy, acyl,substituted or unsubstituted aralkyl or R⁵ forms a bond together withR⁴; R⁶ may be hydrogen atom or substituted or unsubstituted groupsselected from alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl groups, and a process for itspreparation and its use in the preparation of β-aryl-α-oxysubstitutedalkylcarboxylic acids is provided (Scheme-III).

The reaction of a compound of formula (IIIa) where all symbols are asdefined earlier with a compound of formula (IVh) where R⁶ is as definedearlier excluding hydrogen and Hal represent a halogen atom such as Cl,Br, I to produce a compound of formula (IVi) where all symbols aredefined earlier and R⁶ is as defined earlier excluding hydrogen may becarried out under conventional conditions in the presence of a base. Thebase is not critical. Any base normally employed for Wittig reaction maybe employed, metal hydride such as NaH, KH, metal alkoxides such asNaOMe, K^(t)BuO⁻, NaOEt, metal amides such as LiNH₂, LiN(iPr)₂. Aproticsolvent such as THF, DMSO, dioxane, DME and the like may be used.Mixture of solvents may be used. HMPA may be used as cosolvent. Inertatmosphere may be employed such as argon and the reaction is moreeffective under anhydrous conditions. Temperature in the range of −80°C. to 100° C. may be used.

The compound of formula (IVi) where all symbols are as defined earlierand R⁶ is as defined earlier excluding hydrogen may be converted to acompound of formula (IVj) where R⁴ and R⁵ represent hydrogen atoms, R⁶is as defined earlier excluding hydrogen and all other symbols are asdefined earlier, by treating with an alcohol under anhydrous conditionsin the presence of a strong anhydrous acid such as p-toluenesulfonicacid.

The compound of formula (IVj) defined above upon treatment withtrialkylsilyl cyanide such as trimethylsilyl cyanide produces a compoundof formula (IVf) where R⁴ and R⁵ represent hydrogen atoms, R⁶ is asdefined earlier excluding hydrogen and all other symbols are as definedearlier.

In still another embodiment of the present invention there is providedthe novel intermediates of formula (IVg)

where X represents O or S; the groups R¹, R² and the group R³ whenattached to the carbon atom, may be same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; R³ when attached to nitrogen atom representshydrogen, hydroxy, formyl or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives or sulfonic acid derivatives; the linkinggroup represented by —(CH₂)_(n)—O— may be attached either throughnitrogen atom or through carbon atom where n is an integer ranging from1-4; Ar represents a substituted or unsubstituted, divalent, single orfused, aromatic or heterocyclic group; R⁴ represents hydrogen atom,halogen, hydroxy, lower alkyl, alkoxy or substituted or unsubstitutedaralkyl group; R⁷ may be hydrogen or substituted or unsubstituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroarylor heteroaralkyl groups and a process for its preparation and its use inthe preparation of β-aryl-α-oxysubstituted alkylcarboxylic acids isprovided.

The compound of formula (IVg) where all other symbols are as definedearlier may be prepared by reacting a compound of formula (IVk)

where R⁵ is hydrogen atom and all other symbols are as defined earlier,with an appropriate diazotizing agent.

The diazotization reaction may be under conventional conditions. Asuitable diazotizing agent is an alkyl nitrile, such as iso-amylnitrile. The reaction may be carried out in presence of solvents such asTHF, dioxane, ether, benzene and the like or a combination thereof.Temperature in the range of −50° C. to 80 may be used. The reaction maybe carried out in an inert atmosphere which may be maintained by usinginert gases such as N₂, Ar or He. The duration of the reaction may rangefrom 1 to 24 h, preferably, 1 to 12 h.

The compound of formula (IVk) may also be prepared by a reaction between(IIIh) where all symbols are as defined earlier and a compound offormula (IVl)

where R⁵ is hydrogen atom and all other symbols are as defined earlier.

The reaction of compound of formula (IIIh) where all symbols are asdefined earlier and a compound of formula (IVl) where all symbols are asdefined earlier may be carried out in the presence of solvents such asTHF, DMF, DMSO, DME and the like or mixtures thereof. The reaction maybe carried out in an inert atmosphere which is maintained by using inertgases such as N₂, Ar or He. The reaction may be effected in the presenceof a base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof. Acetone maybe used as a solvent when K₂CO₃ or Na₂CO₃ is used as a base. Thereaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours.

In another embodiment of the present invention there is provided thenovel intermediate of formula (IIIm)

where X represents O or S; the groups R¹ and R² may be same or differentand represent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; R³ represents hydrogen, hydroxy, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl,alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonicacid derivatives; n is an integer ranging from 1-4; Ar represents asubstituted or unsubstituted, divalent, single or fused, aromatic orheterocyclic group; R⁴ represents hydrogen atom, halogen, hydroxy, loweralkyl, alkoxy, substituted or unsubstituted aralkyl group or forms abond together with the adjacent group R⁵; R⁵ represents hydrogen,hydroxy, halogen, lower alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl or R⁵ forms a bond together with R⁴; R⁶ may behydrogen atom or substituted or unsubstituted groups selected fromalkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, or arylaminocarbonyl groups; R⁷ may be hydrogen orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups and aprocess for its preparation and its use in the preparation ofβ-aryl-α-oxysubstituted alkylcarboxylic acids is provided.

The compound of formula (IIIm) where all symbols are as defined earliermay be prepared by reacting a compound of formula (IIIn)

where all symbols are as defined earlier, with a compound of formula(IIIo)

where L² is halogen, —OH, —OR¹⁰, —O—C(═O)—OR¹⁰, where R¹⁰ is(C₁-C₅)alkyl and R³ is as defined earlier.

The reaction of compound of general formula (IIIn), where R⁷ is asdefined earlier excluding hydrogen and all other symbols are as definedabove with a compound of formula (IIIo) where all symbols are as definedabove to produce a compound of general formula (IIIm), all symbols areas defined above may be carried out in neat or in the presence ofsolvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSOand the like or mixtures thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The reaction may be carried out at a temperature in therange of −10° C. to 80° C., preferably at a temperature in the range of0° C. to 60° C. The reaction may be effected in the presence or inabsence of a base or an acid. The nature of the base or the acid is notcritical. Bases such as pyridine, lutidine, triethyl amine,diisopropylethyl amine and the like, and acids such as AcOH, C₂H₅COOH,butyric acid, trifluoroacetic acid, p-toluenesulfonic acid,benzenesulfonic acid and the like, may be used. The duration of thereaction may range from 0.25 to 24 hours, preferably from 0.50 to 6hours.

In yet another embodiment of the present invention there is provided thenovel intermediate of formula (IIIn)

where X represents O or S; the groups R¹ and R² may be same or differentand represent hydrogen, halogen, hydroxy, nitro, cyano, formyl orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonicacid or its derivatives; n is an integer ranging from 1-4; Ar representsa substituted or unsubstituted, divalent, single or fused, aromatic orheterocyclic group; R⁴ represents hydrogen atom, halogen, hydroxy, loweralkyl, alkoxy, substituted or unsubstituted aralkyl group or forms abond together with the adjacent group R⁵; R⁵ represents hydrogen,hydroxy, halogen, lower alkyl, alkoxy, acyl, substituted orunsubstituted aralkyl or R⁵ forms a bond together with R⁴; R⁶ may behydrogen atom or substituted or unsubstituted groups selected fromalkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, or arylalinocarbonyl groups; R⁷ may be hydrogen orsubstituted or unsubstituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups and aprocess for its preparation and its use in the preparation ofβ-aryl-α-oxysubstituted alkylcarboxylic acids is provided.

The compound of formula (IIIn) where all symbols are as defined abovemay be prepared by reacting a compound of formula (IVm)

where all symbols are as defined earlier with a compound of formula(IVo)

The reaction of compound of formula (IVm) where all symbols are asdefined earlier with a compound of formula (IVo) where R¹, R² and X areas defined earlier to produce a compound of formula (IIIn) definedearlier may be carried out neat or in the presence of solvents such asxylene, toluene, dioxane, THF, DMF, DMSO, DME and the like or theirmixtures. The reaction may be carried out in an inert atmosphere whichis maintained by using inert gases such as N₂, Ar or He. The reactiontemperature may range from 0° C.-150° C., preferably at a temperature inthe range of 0° C.-120° C. The duration of the reaction may range from0.5 to 12 hours, preferably from 0.5 to 6 hours.

In still another embodiment of the present invention there is providedthe novel intermediates of formula (IVn)

where n is an integer ranging from 1-4; Ar represents a substituted orunsubstituted, divalent, single or fused, aromatic or heterocyclicgroup; R⁴ represents hydrogen atom, hydroxy, alkoxy, halogen, loweralkyl, substituted or unsubstituted aralkyl group or forms a bondtogether with the adjacent group R⁵; R⁵ represents hydrogen, hydroxy,alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstitutedaralkyl or R⁵ forms a bond together with R⁴; R⁶ may be hydrogen,substituted or unsubstituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,heteroaralkyl groups; R⁷ may be hydrogen or substituted or unsubstitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl groups.

The compound of formula (IVn) may be prepared by treating a compound ofgeneral formula (IIId) where all symbols are as defined earlier withappropriate azides such as alkali metal azides like sodium azide,trialkylsilyl azide under conventional conditions. The reaction may becarried out neat or in the presence of solvents such as DMF, acetone,and the like or their mixtures. The reaction temperature may range from0° C. to 150° C., preferably at a temperature in the range of 25° C. to100° C. The duration of the reaction may be range from 0.5 to 48 h,preferably from 1 to 12 h.

Alternatively, the compound of general formula (IVn) where R⁴ and R⁵represent a bond and all other symbols are as defined earlier may beprepared by reacting a compound of formula (IIIb)

where R⁶, R⁷ are as defined earlier excluding hydrogen and R⁹ represents(C₁-C₆)alkyl with a compound of formula (IVp)N₃—(CH₂)_(n)—O—Ar—CHO   (IVp)where all symbols are as defined earlier, to yield a compound of generalformula (IVn) where all symbols are as defined above may be carried outneat in the presence of a base such as alkali metal hydrides like NaH,KH or organolithiums like CH₃Li, BuLi and the like or alkoxides such asNaOMe, NaOEt, BuO⁻K⁺ or mixtures thereof. The reaction may be carriedout in the presence of solvents such as THF, dioxane, DMF, DMSO, DME andthe like or mixtures thereof. HMPA may be used as cosolvent. Thereaction temperature may range from −78° C. to 50° C., preferably at atemperature in the range of −10° C. to 30° C. The reaction is moreeffective under anhydrous conditions.

It is appreciated that in any of the above mentioned reactions, anyreactive group in the substrate molecule may be protected according toconventional chemical practice. Suitable protecting groups in any of theabove mentioned reactions are those used conventionally in the art. Themethods of formation and removal of such protecting groups are thoseconventional methods appropriate to the molecule being protected.

The pharmaceutically acceptable salts are prepared by reacting thecompounds of formula (I) or (IIIm) wherever applicable with 1 to 4equivalents of a base such as sodium hydroxide, sodium methoxide, sodiumhydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxideand the like, in solvents like ether, THF, methanol, t-butanol, dioxane,isopropanol, ethanol etc. Mixture of solvents may be used. Organic baseslike lysine, arginine, diethanolamine, choline, tromethamine, guanidineand their derivatives etc. may also be used. Alternatively, acidaddition salts wherever applicable are prepared by treatment with acidssuch as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, aceticacid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid,ascorbic acid, palmitic acid, succinic acid, benzoic acid,benzenesulfonic acid, tartaric acid and the like in solvents like ethylacetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solventsmay also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphor-sulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR⁸represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, aminoacids, aminoalcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide; the diastereomers may be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

Various polymorphs of compounds of general formula (I) or (IIIm) formingpart of this invention may be prepared by crystallization of compound offormula (I) or (IIIm) under different conditions. For example, usingdifferent solvents commonly used or their mixtures for crystallization;crystallizations at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallizations.Polymorphs may also be obtained by heating or melting the compoundfollowed by gradual or fast cooling. The presence of polymorphs may bedetermined by solid probe NMR spectroscopy, IR spectroscopy,differential scanning calorimetry, powder X-ray diffraction or suchother techniques.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I) or (IIIm),as-defined above, their derivatives, their analogs, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts, their pharmaceutically acceptable solvates incombination with the usual pharmaceutically employed carriers, diluentsand the like, useful for the treatment and/or prophylaxis of diseasessuch as hypertension, coronary heart disease, atherosclerosis, stroke,peripheral vascular diseases and related disorders. These compounds areuseful for the treatment of familial hypercholesterolemia,hypertriglyceridemia, lowering of atherogenic lipoproteins, VLDL andLDL. The compounds of the present invention can be used for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,retinopathy, and nephropathy. The compounds of general formula (I) arealso useful for the treatment/prophylaxis of insulin resistance (type IIdiabetes), leptin resistance, impaired glucose tolerance, dyslipidemia,disorders related to syndrome X such as hypertension, obesity, insulinresistance, coronary heart disease, and other cardiovascular disorders.These compounds may also be useful as aldose reductase inhibitors, forimproving cognitive functions in dementia, treating diabeticcomplications, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS), inflammatory boweldiseases, osteoporosis, myotonic dystrophy, pancreatitis,arteriosclerosis, xanthoma and for the treatment of cancer. Thecompounds of the present inventions are useful in the treatment and/orprophylaxis of the above said diseases in combination/concomittant withone or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramine, colestipol, or probucol.The compounds of the present invention in combination with HMG CoAreductase inhibitors, hypolipidemic/hypolipoproteinemic agents can beadministered together or within such a period to act synergistically.The HMG CoA reductase inhibitors may be selected from those used for thetreatment or prevention of hyperlipidemia such as lovastatin,provastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin andtheir analogs thereof. Suitable fibric acid derivative may begemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrate andtheir analogs thereof.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavourants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%, preferably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

The compounds of the formula (I) or (IIIm) as defined above areclinically administered to mammals, including man, via either oral orparenteral routes. Administration by the oral route is preferred, beingmore convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the patient cannot swallowthe medication or absorption following oral administration is impaired,as by disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 100 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions, may, if desired, contain additional components such asflavourants, sweeteners, excipients and the like. For parenteraladministration, the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically acceptable acid addition salts or salts with base ofthe compounds. The injectable solutions prepared in this manner can thenbe administered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

EXAMPLE 1 (±)Ethyl2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate

To a stirred suspension of NaH (300 mg, 0.0123 mmol, 60%) in dry DMF (20mL) at 0° C. was added a solution of (±)2-ethyl-4-phenyl-1,6-dihydropyrimidin-6-one (1.9 g, 0.0095 mmol) in dryDMF (5 mL). The solution was allowed to stir at room temperature for 20min. after the effervescence cease. LiBr (1.0 g, 0.012 mmol) was addedfollowed by ethyl 2-ethoxy-3-[4-(2-bromoethoxy)phenyl]propanoate (3.2 g,0.0095 mmol) (disclosed in U.S. patent application Ser. No. 09/012,585),in dry DMF at room temperature. The reaction mixture was immersed in apreheated oil bath at 80° C. and stirred for 18 h and cooled to roomtemperature, poured into water and extracted with ethyl acetate (3×10mL). The combined ethyl acetate layers were washed with brine, dried(Na₂SO₄) and concentrated. The crude compound was chromatographed oversilica gel using ethyl acetate:per. ether (3:7) to yield the titlecompound as a liquid (900 mg, 21%).

¹H NMR (CDCl₃): δ 8.01-7.98 (m, 2 H), 7.50-7.43 (m, 3 H), 7.12 (d,J=8.31 Hz, 2 H), 6.78 (s, 1 H), 6.75 (d, J=8.31 Hz, 2 H), 4.47 (t,J=4.89 Hz, 2H), 4.30 (t, J=4.89 Hz, 2 H), 4.15 (q, J=7.15 Hz, 2 H), 3.93(t, J=6.65 Hz, 1 H), 3.62-3.26 (m, 2 H), 3.12 (q, J=7.29 Hz, 2 H), 2.90(d, J=6.65 Hz, 2 H), 1.45 (t, J=7.29 Hz, 3H), 1.25-1.09 (m, 6 H).

The compounds given in Table 1 were also prepared using a similar methoddescribed in Example 1: TABLE 1 Example mp or No. Structure nature Yield¹H NMR (CDCl₃):δ  2

Liquid 39% 7.95-7.92 (m, 2H), 7.46-7.43 (m, 3H), 7.12 (d, J=8.39 Hz,2H), 6.79-6.75 (m, 3H), 4.46 (t, J=4.56 Hz, 2H), 4.31 (t, J=4.56 Hz,2H), 4.18 (q, J=7.15 Hz, 2H), 3.92 (t, J=6.32 Hz, 1H), 3.65-3.26 (m,2H), 2.92 (d, J=6.32 Hz, 2H), 2.82 (s, 3H), 1.36-1.13 (m, 6H).  3

Liquid 18% 8.05-7.97 (m, 2H), 7.47-7.43 (m, 3H), 7.15-7.11 (d, J=8.40Hz, 2H), 6.79-6.75 (m, 3H), 4.50-4.47 (t, J=4.70 Hz, 2H), 4.30 (t,J=4.70 Hz, 2H), 4.17 (q, J=7.15 Hz, 2H), 3.93 (t, J=6.55 Hz, 1H),3.60-3.20 (m, 2H), 3.03 (t, J=7.15 Hz, 2H), 2.92 (d, J=6.55 Hz, 2H),1.96 (q, J=7.47 Hz, 2H), 1.25-1.08 (m, 9H).  4

White solid 40% 7.60-7.40 (m, 5H), 7.13 (d, J=8.30 Hz, 2H), 6.78 (d,J=8.30 Hz, 2H), 4.46 (t, J=4.98 Hz, 2H), 4.31 (t, J=4.98 Hz, 2H), 4.15(q, J=7.06 Hz, 2H), 3.94 (t, J=6.65 Hz, 1H), 3.70-3.25 (m, 2H), 3.02 (q,J=7.47 Hz, 2H), 2.93 (d, J=6.65 Hz, 2H), 2.52 (q, J=7.15 Hz, 2H),1.50-1.15 (m, 12H).  5

Liquid 10% 8.03-7.95 (m, 2H), 7.50-7.40 (m, 3H), 7.12 (d, J=8.30 Hz,2H), 6.76 (s, 1H), 6.75 (d, J=8.30 Hz, 2H), 4.51 (t, J=4.98 Hz, 2H),4.27 (t, J=4.98 Hz, 2H), 4.14 (q, J=7.15 Hz, 2H), 3.92 (t, J=6.74 Hz,1H), 3.70-3.20 (m, 2H), 3.16-3.00 (m, 1H), 2.91 (d, J=6.74 Hz, 2H), 1.42(s, 3H), 1.40 (s, 3H), 1.30-1.14 (m, 6H).  6

Gummy liquid 25% 7.12 (d, J=8.70 Hz, 2H), 6.75 (d, J=8.70 Hz, 2H), 6.18(s, 1H), 4.38 (t, J=5.00 Hz, 2H), 4.22 (t, J=5.00 Hz, 2H), 4.15 (q,J=10.50 Hz, 2H), 3.94 (t, J=7.00 Hz, 1H), 3.65-3.20 (m, 2H), 3.00-2.85(m, 4H), 2.21 (s, 3H), 1.90-1.70 (m, 2H), 1.30-1.00 (m, 9H).  7

Colorless liquid 32% 7.15 (d, J=8.62 Hz, 2H), 6.85 (d, J=8.62 Hz, 2H),6.40 (s, 1H), 4.68 (t, J=4.77 Hz, 2H), 4.27 (t, J=4.77 Hz, 2H), 4.16 (q,J=7.35 Hz, 2H), 3.95 (t, J=6.61 Hz, 1H), 3.70-3.25 (m, 2H), 2.95 (d,J=6.61 Hz, 2H), 2.57 (s, 3H), 2.39 (s, 3H), 1.35-1.10 (m, 6H).  8

Liquid 21% 7.13 (d, J=8.45 Hz, 2H), 6.74 (d, J=8.45 Hz, 2H), 6.69 (s,1H), 4.46 (t, J=4.77 Hz, 2H), 4.27 (t, J=4.77 Hz, 2H), 4.15 (q, J=7.15Hz, 2H), 3.93 (t, J=6.48 Hz, 1H), 3.62-3.20 (m, 2H), 3.12 (q, J=7.26 Hz,2H), 2.92 (d, J=6.48 Hz, 2H), 1.40-1.10 (m, 9H).  9

Liquid 14% 8.04-7.99 (m, 2H), 7.49-7.46 (m, 3H), 7.14 (d, J=8.62 Hz,2H), 6.93 (s, 1H), 6.86 (d, J=8.62 Hz, 2H), 4.56-4.40 (m, 4H), 4.18 (q,J=7.15 Hz, 2H), 3.97 (t, J=6.62 Hz, 1H), 3.65-3.25 (m, 4H), 2.94 (d,J=6.62 Hz, 2H), 1.42 (t, J=7.10 Hz, 3H), 1.25-1.10 (m, 6H). 10

Gummy liquid 25% 8.10-7.97 (m, 2H), 7.20-7.10 (m, 2H), 7.12 (d, J=8.49Hz, 2H), 6.75 (d, J=8.49 Hz, 2H), 6.72 (s, 1H), 4.47 (t, J=4.77 Hz, 2H),4.29 (t, J=4.77 Hz, 2H), 4.15 (q, J=7.15 Hz, 2H), 3.92 (t, J=6.46 Hz,1H), 3.65-3.20 (m, 2H), 3.09 (q, J=7.47 Hz, 2H), 2.92 (d, J=6.46 Hz,2H), 1.44 (t, J=7.47 Hz, 3H), 1.30-1.10 (m, 6H). 11

Gummy liquid 22% 7.94 (d, J=8.40 Hz, 2H), 7.41 (d, J=8.40 Hz, 2H), 7.12(d, J=8.40 Hz, 2H), 6.75 (d, J=8.40 Hz, 2H), 6.74 (s, 1H), 4.46 (t,J=4.66 Hz, 2H), 4.28 (t, J=4.66 Hz, 2H), 4.15 (q, J=6.92 Hz, 2H), 3.92(t, J=6.55 Hz, 1H), 3.65-3.20 (m, 2H), 3.09 (q, J=7.47 Hz, 2H), 2.91 (d,J=6.55 Hz, 2H), 1.45 (t, J=7.24 Hz, 3H), 1.30-1.10 (m, 6H). 12

liquid 59% 7.16 (d, J=8.62 Hz, 2H), 6.86 (d, J=8.62 Hz, 2H), 6.43 (s,1H), 4.70 (t, J=4.77 Hz, 2H), 4.28 (t, J=4.77 Hz, 2H), 4.17 (q, J=7.11Hz, 2H), 3.96 (t, J=6.55 Hz, 1H), 3.70-3.50 (m, 1H), 3.42-3.22 (m, 1H),2.95 (d, J=6.55 Hz, 2H), 2.83 (q, J=7.60 Hz, 2H), 2.40 (s, 3H), 1.32 (t,J=7.60 Hz, 3H), 1.23 (t, J=7.11 Hz, 3H), 1.63 (t, J=6.90 Hz, 3H).

EXAMPLE 13 (±)2-Ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid

To the methanolic (15 mL) solution of(±)ethyl-2-ethoxy-3-[4-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoate(420 mg, 0.909 mmol) obtained in example 1 was added NaOH (365 mg, 9.125mmol) in H₂O (10 nL), the mixture was stirred at 250C for 1 hr,evaporated the solvent under reduced pressure. The residue was added to50 mL of cold water and washed with ethyl acetate (2×50 mL). The aqueouslayer was acidified with 2N HCl and extracted with ethyl acetate (3×100mL). The combined ethyl acetate layers were washed with water, brine,dried (Na₂SO₄) and evaporated the solvent, to give a stick compound,which was solidified by either long drying under vacuum or triturationwith dry ether to give a white solid (380 mg, 96%) mp: 138-140° C.

¹H NMR (CDCl₃): δ 8.03-7.98 (m, 2 H), 7.47-7.44 (m, 3H), 7.13 (d, J=8.63Hz, 2 H), 6.81 (s, 1H), 6.76 (d, J=8.63 Hz, 2 H), 4.46 (t, J=4.98 Hz, 2H), 4.31 (t, J=4.98 Hz, 2 H), 4.09-3.95 (m. 1 H), 3.65-3.35 (m, 2H),3.15-2.85 (m, 4H), 1.46 (t, J=7.29 Hz, 3 H), 1.18 (t, J=7.06 Hz, 3 H).

The compounds given in Table 2 were also prepared using a similar methoddescribed in Example 14: TABLE 2 Example mp or ¹H NMR No. Structurenature Yield (CDCl₃):δ 14

White hygroscopic solid 108-110° C. 56% 7.97-7.93 (m, 2H), 7.47-7.44 (m,3H), 7.14 (d, J=8.63 Hz, 2H), 6.80 (d, J=8.63 Hz, 2H), 6.78 (s, 1H),4.48 (t, J=4.50 Hz, 2H), 4.31 (t, J=4.50 Hz, 2H), 4.05-3.99 (m, 1H),3.56-3.43 (m, 2H), 3.05 (dd, J=4.24 Hz and 14.12 Hz, 1H), 2.92 (dd,J=7.48 Hz and 14.12 Hz, 1H), 2.82 (s, 3H), 1.16 (t, 6.92 Hz, 3H) 15

White solid 132-134° C. 30% 8.01-7.90 (m, 2H), 7.50-7.40 (m, 3H), 7.15(d, J=8.30 Hz, 2H), 6.81 (s, 1H), 6.79 (d, J=8.30 Hz, 2H), 4.49 (t,J=4.67 Hz, 2H), 4.32 (t, J=4.67 Hz, 2H), 4.10-3.90 (m, 1H), 3.70-3.30(m, 2H), 3.15-2.80 (m, 4H), 1.98 (q, J=7.58 Hz, 2H), 1.40-1.10 (m, 6H)16

White solid 54% 7.55-7.40 (m, 5H), 7.14 (d, J=8.31 Hz, 2H), 6.80 (d,J=8.31 Hz, 2H), 4.47 (t, J=4.77 Hz, 2H), 4.32 (t, J=4.77 Hz, 2H),4.10-4.00 (m, 1H), 3.70-3.40 (m, 2H), 3.10-2.90 (m, 4H), 2.52 (q, J=7.38Hz, 2H), 1.35 (t, J=7.25 Hz, 3H), 1.25-1.10 (m, 6H) 17

White solid 82-84° C. 27% 8.04-8.01 (m, 2H), 7.48-7.45 (m, 3H), 7.15 (d,J=8.53 Hz, 2H), 6.84 (s, 1H), 6.77 (d, J=8.53 Hz, 2H), 4.55 (t, J=4.77Hz, 2H), 4.29 (t, J=4.77 Hz, 2H), 4.04-3.98 (m, 1H), 3.76-3.36 (m, 3H),3.05 (dd, J=4.25 and 13.70 Hz, 1H), 2.95 (dd, J=6.13 and 13.70 Hz, 1H),1.44 (s, 3H), 1.41 (s, 3H), 1.16 (t, J=6.82 Hz, 3H) 18

White solid 106-110° C. 79% 7.13 (d, J=8.39 Hz, 2H), 6.74 (d, J=8.39 Hz,2H), 6.20 (s, 1H), 4.41 (t, J=4.78 Hz, 2H), 4.25 (t, J=4.78 Hz, 2H),4.04-3.98 (m, 1H), 3.65-3.30 (m, 2H), 3.10-2.85 (m, 4H), 2.23 (s, 3H),1.90-1.65 (m, 2H), 1.15 (t, J=7.04 3H), 105 (t, J=7.40 Hz, 3H) 19

White fluffy hygroscopic solid 126-128° C. 34% 7.16 (d, J=8.63 Hz, 2H),6.84 (d, J=8.63 Hz, 2H), 6.47 (s, 1H), 4.71 (t, J=4.60 Hz, 2H), 4.27 (t,J=4.60 Hz, 2H), 4.07-4.01 (m, 1H), 3.65-3.38 (m, 2H), 3.08 (dd, J=4.34and 14.12 Hz, 1H), 2.95 (dd, J=6.74 and 14.12 Hz, 1H), 2.62 (s, 3H),2.45 (s, 3H), 1.18 (t, J=7.00 Hz, 3H) 20

White solid 124-126° C. 58% 7.13 (d, J=8.39 Hz, 2H), 6.75 (d, J=8.39 Hz,2H), 6.70 (s, 1H), 4.46 (t, J=4.65 Hz, 2H), 4.27 (t, J=4.65 Hz, 2H),4.06-4.00 (m, 1H), 3.60-3.40 (m, 2H), 3.20-2.90 (m, 4H), 1.38 (t, J=7.40Hz, 3H), 1.18 (t, J=7.00 Hz, 3H) 21

Colorless liquid 41% 8.10-7.95 (m, 2H), 7.55-7.40 (m, 3H), 7.13 (d,J=8.63 Hz, 2H), 6.92 (s, 1H), 6.87 (d, J=8.63 Hz, 2H), 4.60-4.40 (m,4H), 4.15-4.00 (m, 1H), 3.70-3.45 (m, 2H), 3.38 (t, J=6.83 Hz, 2H), 3.10(dd, J=4.15 and 18.58 Hz, 1H), 2.95 (dd, J=7.38 and 18.58 Hz, 1H), 1.41(t, J=7.05 Hz, 3H), 1.18 (t, J=6.83 Hz, 3H) 22

White solid 110-114° C. 54% 8.10-7.90 (m, 2H), 7.20-7.10 (m, 2H), 7.12(d, J=8.64 Hz, 2H), 6.76 (d, J=8.64 Hz, 2H), 6.73 (s, 1H), 4.47 (t,J=4.31 Hz, 2H), 4.30 (t, J=4.31 Hz, 2H), 4.10-3.98 (m, 1H), 3.62-3.35(m, 2H), 3.15-2.85 (m, 4H), 2.00 (bs, D₂O exchangeable, 1H,), 1.44 (t,J=7.38 Hz, 3H), 1.16 (t, J=6.96 Hz, 3H) 23

Pale yellow solid 62-64° C. 68% 7.95 (d, J=8.63 Hz, 2H), 7.42 (d, J=8.54Hz, 2H), 7.13 (d, J=8.63 Hz, 2H), 6.77 (d, J=8.54 Hz, 2H), 6.75 (s, 1H),4.47 (t, J=4.80 Hz, 2H), 4.30 (t, J=4.80 Hz, 2H), 4.10-3.95 (m, 1H),3.65-3.35 (m, 2H), 3.15-2.85 (m, 4H), 1.44 (t, J=7.38 Hz, 3H), 1.16 (t,J=7.01 Hz, 3H) 24

white solid 100-103° C. 50% 7.19 (d, J=8.62 Hz, 2H), 6.88 (d, J=8.62 Hz,2H), 6.45 (s, 1H), 4.73 (t, J=4.79 Hz, 2H), 4.30 (t, J=4.79 Hz, 2H),4.06 (dd, J=7.28, 4.56 Hz, 1H), 3.70-3.40 (m, 2H), 3.11 (dd, J=14.16,4.56 Hz, 1H), 2.97 (dd, J=14.16 and 7.28 Hz, 1H), 2.85 (q, J=7.58 Hz,2H), 2.42 (s, 3H), 1.33 (t, J=7.58 Hz, 3H), 1.20 (t, J=7.01 Hz, 3H).

EXAMPLE 25 [2R,N(1S)]-2ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(25a)

[2S,N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(25b)

To a solution of (±)2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid (1 g, 2.37 mmol) obtained in example 13 in dry dichloromethane (10mL) was added triethyl amine (600 mg, 5.92 mmol). The reaction mixturewas cooled to 0° C. and pivaloyl chloride (314 mg, 2.6 mmol) was added.The reaction mixture was stirred at25° C. for 0.5 h until all the acidis converted to mixed anhydride, followed by addition of S(+)2-phenylglycinol (375 mg, 2.6 mmol) and triethyl amine (600 mg, 5.92mmol) in dry dichloromethane (10 mL). After stirring the reactionmixture at about 25° C. for 2h, water was added and extracted withdichloromethane. The organic extracts were washed with water and brine,dried (Na₂SO₄) and evaporated. The residue was purified by silica gelcolumn chromatography using a gradient of 50-80% ethyl acetate in petether as an eluent to afford a diastereomer tentatively assigned as[2R,N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide (25a) (400 mg, followed by[2S,N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(25b) as a viscous liquid (400 mg).

25a: [α]²⁵ _(D)=18.2 (c=1.0, CHCl₃) 98% d .e (by HPLC); ¹H NMR (CDCl₃)δ: 8.10-7.95 (m, 2 H), 7.60-7.40 (m, 3 H), 7.25 (d, J=8.30 Hz, 2 H),7.10-7.00 (m, 5 H), 6.81 (s, 1 H), 6.70(d, J=8.30 Hz, 2 H), 4.99-4.96(m, 1 H), 4.42 (t, J=4.60 Hz, 2 H), 4.25 (t, J=4.60 Hz, 2 H), 4.00-3.92(m, 1 H), 3.80 (d, J=4.66 Hz, 2 H), 3.60-3.40 (m, 2 H), 3.13 (q, J=7.38Hz, 2 H), 3.02 (dd, J=3.32 Hz and 13.33 Hz, 1 H), 2.85 (dd, J=6.74 Hzand 13.33 Hz, 1 H), 1.47 (t, J=7.38 Hz, 3 H), 1.16 (t, J=7.00 Hz, 3 H).

25b: viscous liquid, [α]²⁵ _(D)=−16.0 (c=1.0, CHCl₃) 98.5% d .e (byHPLC); ¹H NMR (CDCl₃) δ: 8.00-7.90 (m, 2 H), 7.56-7.40 (m, 3 H), 7.25(d, J=8.27 Hz, 2 H), 7.05-6.95 (m, 5 H), 6.80 (s, 1 H), 6.67(d, J=8.27Hz, 2 H), 4.95-4.90 (m, 1 H), 4.38 (t, J=4.60 Hz, 2 H), 4.22 (t, J=4.60Hz, 2 H), 4.00-3.90 (m, 1 H), 3.88 (d, J=4.64 Hz, 2 H), 3.60-3.40 (m, 2H), 3.10 (q, J=7.42 Hz, 2 H), 3.00 (dd, J=4.30 Hz and 13.42 Hz, 1 H),2.85 (dd, J=6.72 Hz and 13.42 Hz, 1 H), 1.50 (t, J=7.40 Hz, 3 H), 1.18(t, J=7.02 Hz, 3 H).

EXAMPLE 26 (−)2-Ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxyl]phenyl]propanoicacid

A solution of[2S,N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(295 mg, 0.53 mmol) obtained in example 25 in a mixture of 1M sulfuricacid (7.7 mL) and dioxane/water (1:1, 14 mL) was heated at 90° C. for 48h and the pH of the mixture was adjusted to 4 by the addition of aqueoussodium bicarbonate solution. The mixture was extracted with ethylacetate and the combined ethyl acetate layers were washed with water,brine, dried (Na₂SO₄) and evaporated to yield a colorless solid (43%) mp140-142° C.

[α]²⁵ _(D)=−9.2; ¹H NMR (CDCl₃): δ8.05-7.95 (m, 2 H), 7.52-7.40 (m, 3H), 7.13 (d, J=8.40 Hz, 2H), 6.80 (s, 1H), 6.78 (d, J=8.40 Hz, 2H), 4.49(t, J=4.71 Hz, 2H), 4.31 (t, J=4.71 Hz, 2H), 4.10-4.00 (m, 1H),3.65-3.35 (m, 2H), 3.12 (q, J=7.15 Hz, 2H), 3.01 (dd, J=4.66 Hz and 11.2Hz, 1H), 2.95 (dd, J=9.2 Hz, 14.2 Hz, 1H), 2.00 (bs, D₂O exchangeable1H), 1.46 (t, J=7.15 Hz, 3H), 1.16 (t, J=6.92 Hz, 3H).

EXAMPLE 27 (+)2-Ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid

The title compound (28%) was prepared from a solution of[2R,N(1S)]-2-ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethly)propanamideobtained in example 25 (223 mg, 0.540 mmol) by a similar method asdescribed in example 26, mp 145-147° C.

[α]²⁵ _(D)=+11.00; ¹H NMR (CDCl₃): δ 8.02-7.97 (m, 2H), 7.50-7.40 (m,3H), 7.15 (d, J=8.54 Hz, 2H), 6.81 (s, 1H), 6.80 (d, J=8.54 Hz, 2H),4.50 (t, J=4.88 Hz, 2H), 4.33 (t, J=4.88 Hz, 2H), 4.10-4.00 (m, 1 H),3.60-3.40 (m, 2H), 3.12 (q, J=7.32 Hz, 2H), 3.07 (d, J=3.91 Hz and 13.43Hz, 1 H), 2.95 (dd, J=7.32 Hz and 13.43 Hz and 1 H), 2.00 (bs, D₂Oexchangeable, 1H), 1.48 (t, J=7.32 Hz, 3H), 1.18 (t, J=6.83 Hz, 3H).

EXAMPLE 28 (±)2-Ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid, magnesium salt

To a stirred solution of (±)2-ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid obtained in example 14 (100 mg, 0236 mmol) in dry methanol (5 mL)magnesium hydroxide (6.5 mg, 0.168 mmol) was added and allowed to stirat room temperature for 24 h. The solvent was evaporated and trituratedwith dry ether, dried over CaCl₂ to yield the title compound as a whitesolid (100 mg, 99%), mp 158-160° C.

¹H NMR: δ 7.93-7.90 (m, 2H), 7.40-7.37 (m, 3H), 7.07 (d, J=8.30 Hz, 2H),6.73 (d, J=8.30 Hz, 2H), 6.71 (s, 1H), 4.60-4.30 (m, 3H), 4.25 (t,J=4.56 Hz, 2H), 3.80-3.40 (m, 2H), 3.20-2.80 (m, 2H), 2.77 (s, 3H), 1.00(t, J=7.60 Hz, 3H).

EXAMPLE 29

(±)2-Ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid, sodium salt

To a stirred solution of (±)2-ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid obtained in example 14 (100 mg, 0.236 mmol) in dry methanol (1.5mL) sodium methoxide (12.8 mg, 0.236 mmol) in methanol (1.5 mL) wasadded and allowed to stir at room temperature for 12 h. The solvent wasevaporated and washed with 10% methanol in ether solution (3×5 mL) anddried under vacuum for 4 h to yield the title compound as a cream colourhygroscopic solid (70mg, 67%), mp 288-292° C.

¹H NMR (CD₃OD): δ8.06-7.88 (m, 2H), 7.45-7.30 (m, 3H), 7.10 (d, J=8.54Hz, 2H), 6.72 (d, J=8.54 Hz, 2H), 6.71 (s, 1H), 4.40 (t, J=4.98 Hz, 2H),4.24 (t, J=4.98 Hz, 2H), 3.70-3.60 (m, 1H), 3.55-3.35 (m, 1H), 3.26 (s,3H), 3.20-3.05 (m, 1H), 2.85 (dd, J=4.05 Hz and 14.02 Hz, 1H), 2.65 (dd,J=8.72 Hz and 14.02 Hz, 1H), 0.97 (t, J=7.05 Hz, 3H).

EXAMPLE 30

(±)2-Ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid, arginine salt

To a stirred solution of (±)2-ethoxy-3-[4-[2-[2-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidin-1-yl]ethoxy]phenyl]propanoicacid obtained in example 14 (100 mg, 0.24 mmol) in dry methanol (5 mL)L-arginine (40 mg, 0.23 mmol) was added at 25° C. and stirred thereaction mixture over 24 h. The solvent was evaporated at lowtemperature and triturated with dry ether (3×20 mL) and dried undervacuum at 50° C. for 6 h to yield the title compound as slightlyhygroscopic white solid (100 mg, 72%), mp 168-170° C.

¹H NMR (CD₃OD): δ 8.00-7.85 (m, 2H), 7.40-7.30 (m, 3H), 7.08 (d, J=8.30Hz, 2H), 6.72 (d, J=8.30 Hz, 2H), 6.70 (s, 1H), 4.41 (t, J=4.77 Hz, 2H),4.23 (t, J=4.77 Hz, 2H), 3.72-3.60 (m, 1H), 3.55-3.30 (m, 2H), 3.25-3.00(s, 4H), 2.80 (dd, J=4.06 Hz and 13.72 Hz, 1H), 2.70 (dd, J=9.06 Hz and13.72 Hz, 1H), 2.71 (s, 3H), 1.90-1.50 (m, 3H), 0.96 (t, J=7.30Hz, 3H).

The compounds of the present invention lowered random blood sugar level,triglyceride, total cholesterol, LDL, VLDL and increased HDL. This wasdemonstrated by in vitro as well as in vivo animal experiments.

Demonstration of Efficacy of Compounds

A) In vitro:

a) Determination of hPPARα Activity:

Ligand binding domain of hPPARα was fused to DNA binding domain of Yeasttranscription factor GAL4 in eucaryotic expression vector. Usingsuperfect (Qiagen, Germany) as transfecting reagent HEK-293 cells weretransfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat different concentrations after 42 hrs of transfection and incubatedovernight. Luciferase activity as a function of compoundbinding/activation capacity of PPARα was measured using Packard Luclitekit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, PeterBroag and Melvyn Hollis. Gene. 1992. 118: 137-141; SuperfectTransfection Reagent Handbook. February 1997. Qiagen, Germany).

b) Determination of hPPARγ Activity:

Ligand binding domain of hPPARγ1 was fused to DNA binding domain ofYeast transcription factor GAL4 in eucaryotic expression vector. Usinglipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cellswere transfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat 1 μM concentration after 48 hrs of transfection and incubatedovernight. Luciferase activity as a function of drug binding/activationcapacity of PPARγ1 was measured using Packard Luclite kit (Packard, USA)in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag andMelvyn Hollis. Gene. 1992. 118: 137-141; Guide to EukaryoticTransfections with Cationic Lipid Reagents. Life Technologies, GIBCOBRL, USA). PPARα AND PPARγ ACTIVITY Example No Concentration PPARαConcentration PPARγ Example 22 50 μM 7.7 1 μM 23.9 Example 23 50 μM 6.41 μM 19.95

c) Determination of HMG CoA Reductase Inhibition Activity: Livermicrosome bound reductase can be prepared from 2% cholestyramine fedrats at mid-dark cycle. Spectrophotometric assays can be carried out in100 mM KH₂PO4, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg ofliver microsomal enzyme. Total reaction mixture volume can be kept as 1ml and the reaction started by addition of HMG CoA. Reaction mixture canbe incubated at 37° C. for 30 min and decrease in absorbence at 340 nmcan be recorded. Reaction mixture without substrate can be used as blank(Goldstein, J. L and Brown, M. S. Progress in understanding the LDLreceptor and HMG CoA reductase, two membrane proteins that regulate theplasma cholesterol. J. Lipid Res. 1984, 25: 1450-1461). This protocolcan be used to test for compounds that inhibit HMG CoA reductase enzyme.

B) In vivo:

a) Efficacy in Genetic Models:

Mutation in colonies of laboratory animals and different sensitivitiesto dietary regimens have made the development of animal models withnon-insulin dependent diabetes and hyperlipidemia associated withobesity and insulin resistance possible. Genetic models such as db/dband ob/ob (Diabetes, (1982) 31(1): 1-6) mice and Zucker fa/fa rats havebeen developed by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838 ; Annu. Rep. Sankyo Res. Lab.(1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, US, are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwere tested for blood sugar and triglycerides lowering activities.

Male C₅₇BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animalhouse, were used in the experiment. The mice were provided with standardfeed (National Institute of Nutrition (NIN), Hyderabad, India) andacidified water, ad libitum. The animals having more than 350 mg/dlblood sugar were used for testing. The number of animals in each groupwas 4.

Test compounds were suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 0.001 mg to 30 mg/kg throughoral gavage daily for 6 days. The control group received vehicle (dose10 ml/kg). On 6th day the blood samples were collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglyceride levels were measuredspectrometrically, by glucose oxidase and glycerol-3-PO₄oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula given below.

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test. BLOOD GLUCOSE LOWERING ACTIVITY IN DB/DBMICE Reduction in Blood Triglyceride Compound Dose (mg/kg) Glucose Level(%) Lowering (%) Example 14 3 mg 60 46 Example 22 3 mg 64 47 Example 233 mg 63 41

The experimental results from the db/db mice, suggest that the novelcompounds of the present invention also possess therapeutic utility as aprophylactic or regular treatment for diabetes, obesity, cardiovasculardisorders such as hypertension, hyperlipidaemia and other diseases; asit is known from the literature that such diseases are interrelated toeach other.

Blood glucose level and triglycerides are also lowered at doses greaterthan 10 mg/kg. Normally, the quantum of reduction is dose dependent andplateaus at certain dose.

Compounds can be tested in ob/ob mice and Zucker rats as describedbelow.

The ob/ob mice at 5 weeks of age can be obtained from Bomholtgard,Denmark and can be used at 8 weeks of age. Zucker fa/fa fatty rats canbe obtained from IffaCredo, France at 10 weeks of age and can be used at13 weeks of age. The animals can be maintained under 12 hour light anddark cycle at 25±1° C. Animals can be given standard laboratory chow(NIN, Hyderabad, India) and water, ad libitum (Fujiwara, T., Yoshioka,S., Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of neworal antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zuckerfatty rats. Diabetes. 1988. 37: 1549-1558).

The test compounds can be administered at 0.1 to 30 mg/kg/day dose for 9days. The control animals can receive the vehicle (0.25%carboxymethylcellulose, dose 10 ml/kg) through oral gavage.

The blood samples can be collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment. The blood can be collectedfrom the retro-orbital sinus through heparinised capillary in EDTAcontaining tubes. After centrifugation, plasma samples can be separatedfor triglyceride, glucose, free fatty acid, total cholesterol andinsulin estimations. Measurement of plasma triglyceride, glucose, totalcholesterol can be done using commercial kits (Dr. Reddy's Laboratory,Diagnostic Division kits, Hyderabad, India). The plasma free fatty acidcan be measured using a commercial kit from Boehringer Mannheim,Germany. The plasma insulin can be measured using a RIA kit (BARC,India). The reduction of various parameters examined is calculatedaccording to the formula given below.

In ob/ob mice oral glucose tolerance test can be performed after 9 daystreatment. Mice can be fasted for 5 hrs and challenged with 3 gm/kg ofglucose orally and blood samples can be collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

b) Cholesterol Lowering Activity in Hypercholesterolemic Rat Models:

Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.Animals were maintained under 12 hour light and dark cycle at 25±1° C.Rats of 180-200 gram body weight range were used for the experiment.Animals were made hypercholesterolemic by feeding 2% cholesterol and 1%sodium cholate mixed with standard laboratory chow [National Instituteof Nutrition (NIN), Hyderabad, India] for 6 days. Throughout theexperimental period the animals were maintained on the same diet (Petit,D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate onliver lipids and lipoprotein synthesis in normo- and hyperlipidemicrats. Atherosclerosis. 1988. 74: 215-225).

The test compounds were administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 1 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment. The blood wascollected from the retro-orbital sinus through heparinised capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement ofplasma triglyceride, total cholesterol and HDL were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula. CHOLESTEROLLOWERING ACTIVITY IN MALE SPRAGUE RATS Dose Triglyceride Total Compoundmg/kg (%)↓ Cholesterol (%)↓ HDL↑ (%) LDL (%)↓ VLDL(%)↓ Example 15 3 mg52 42 53 46 52↓ = reduction; ↑ = increase; NE = no effect

c) Plasma Triglyceride and Total Cholesterol Lowering Activity in SwissAlbino Mice and Guinea Pigs:

Male Swiss albino mice (SAM) were obtained from NIN and housed in DRFanimal house. All these animals were maintained under 12 hour light anddark cycle at 25±1° C. Animals were given standard laboratory chow (NIN,Hyderabad, India) and water, ad libitum. SAM of 20-25 g body weightrange and Guinea pigs of 500-700 g body weight range were used (Oliver,P., Plancke, M. O., Marzin, D., Clavey, V., Sauzieres, J and Fruchart,J. C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasmalipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis.1988. 70: 107-114).

The test compounds were administered orally to Swiss albino mice at 0.3to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle(0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds wereadministered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6days. Control animals were treated with vehicle (0.25%Carboxymethylcellulose; dose 5 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergermeyer, H. O., Ed., 1963. 211-214; Trinder, P. Ann. Clin.Biochem. 1969. 6: 24-27). Measurement of plasma triglyceride, totalcholesterol and HDL were done using commercial kits (Dr. Reddy'sDiagnostic Division, Hyderabad, India). TRIGLYCERIDE LOWERING ACTIVITYIN SWISS ALBINO MICE Compound Dose (mg/kg) Triglyceride (%)↓ Example 143 mg 46 Example 16 3 mg 38 Example 17 3 mg 48 Example 23 3 mg 54 Example22 3 mg 38

Formulae for Calculation:

1. Percent reduction in Blood sugar/triglycerides/total cholesterol werecalculated according to the formula:${{Percent}\quad{reduction}\quad(\%)} = {\left\lbrack {1 - \frac{{TT}/{OT}}{{TC}/{OC}}} \right\rbrack \times 100}$

-   -   OC=Zero day control group value    -   OT=Zero day treated group value    -   TC=Test day control group value    -   TT=Test day treated group value

2. LDL and VLDL cholesterol levels were calculated according to theformula:${{LDL}\quad{cholesterol}\quad{in}\quad{mg}\text{/}{dl}} = {\left\lbrack {{{Total}\quad{cholesterol}} - {{HDL}\quad{cholesterol}} - \frac{Triglyceride}{5}} \right\rbrack{mg}\text{/}{dl}}$VLDL  cholesterol    in  mg/dl = [Total  cholesterol − HDL  cholesterol − LDL  cholesterol]mg/dl.

1-60. (canceled)
 61. A compound of formula (IVf)

where X represents O or S; the groups R¹, R² and the group R³, whenattached to the carbon atom, are the same or different, and representhydrogen, halogen, hydroxyl, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl selectedfrom the group consisting of aziridinyl, pyrrolidinyl, morpholinyl,piperidinyl and piperazinyl; heteroaryl selected from the groupconsisting of pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl and benzofuranyl;heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or an amide or ester of thecarboxylic acid, or sulfonic acid or an amide or ester of the sulfonicacid; R³ when attached to nitrogen atom represents hydrogen, hydroxyl,formyl or substituted or unsubstituted groups selected from alkyl, cyclo(C₃-C₆)alkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy,heterocyclyl selected from the group consisting of axiridinyl,pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl; heteroarylselected from the group consisting of pyridyl, thienyl, furyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyland benzofuranyl; heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino,arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl groups, an aminde or an ester of carboxylic acide or an amideor an ester of sulfonic acid; the linking group represented by—(CH₂)_(n)—O— is attached either through nitrogen atom or through carbonatom where n is an integer ranging from 1-4; Ar represents a substitutedor unsubstituted, divalent, single or fused, aromatic or heterocyclicgroup selected from the group consisting of divalent phenylene,naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl,benzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl,benzothiazolyl and benzoxazolyl; R⁴ represents hydrogen atom, halogen,hydroxyl, lower alkyl, alkoxy or aralkyl group; R⁵ represents hydrogenor substituted or unsubstituted group selected from alkyl, cyclo(C₃-C₇)alkyl, aryl, aralkyl, heterocyclyl selected from the groupconsisting of aziridinyl, pyrrolidinyl and piperidinyl; heteroarylselected from the group consisting of pyridyl, thienyl and furyl orheteroaralkyl groups; and R⁶ represents hydrogen or substituted orunsubstituted group selected from alkyl, acyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, and alkylaminocarbonyl,arylaminocarbonyl.
 62. A compound of formula (IVg)

where X represents O or S; the groups R¹, R² and the group R³, whenattached to the carbon atom, are the same or different, and representhydrogen, halogen, hydroxyl, nitro, cyano, formyl or substituted orunsubstituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl selectedfrom the group consisting of aziridinyl, pyrrolidinyl, morpholinyl,piperidinyl and piperazinyl; heteroaryl selected from the groupconsisting of pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl and benzofuranyl;heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino,aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino,aralkoxycarbonylamino, carboxylic acid or an amide or ester of thecarboxylic acid, or sulfonic acid or an amide or ester of the sulfonicacid; R³ when attached to nitrogen atom represents hydrogen, hydroxyl,formyl or substituted or unsubstituted groups selected from alkyl, cyclo(C₃-C₆)alkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy,heterocyclyl selected from the group consisting of axiridinyl,pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl; heteroarylselected from the group consisting of pyridyl, thienyl, furyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyland benzofuranyl; heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl,acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino,arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl groups, an aminde or an ester of carboxylic acide or an amideor an ester of sulfonic acid; the linking group represented by—(CH₂)_(n)—O— is attached either through nitrogen atom or through carbonatom where n is an integer ranging from 1-4; Ar represents a substitutedor unsubstituted, divalent, single or fused, aromatic or heterocyclicgroup selected from the group consisting of divalent phenylene,naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl,benzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl,benzothiazolyl and benzoxazolyl; R⁴ represents hydrogen atom, halogen,hydroxyl, lower alkyl, alkoxy or aralkyl group; R⁵ represents hydrogenor substituted or unsubstituted group selected from alkyl, cyclo(C₃-C₇)alkyl, aryl, aralkyl, heterocyclyl selected from the groupconsisting of aziridinyl, pyrrolidinyl and piperidinyl; heteroarylselected from the group consisting of pyridyl, thienyl and furyl orheteroaralkyl groups; and R⁷ represents hydrogen or substituted orunsubstituted group selected from alkyl, acyl, cycloalkyl, aryl,aralkyl, heterocyclyl, heteroaryl, and heteroaralkyl.